Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Musical and vocal emotion perception for cochlear implants users.

Cochlear implants can successfully restore hearing in profoundly deaf individuals and enable speech comprehension. However, the acoustic signal provided is severely degraded and, as a result, many important acoustic cues for perceiving emotion in voices and music are unavailable. The deficit of cochlear implant users in auditory emotion processing has been clearly established. Yet, the extent to which this deficit and the specific cues that remain available to cochlear implant users are unknown due to several confounding factors. Here we assessed the recognition of the most basic forms of auditory emotion and aimed to identify which acoustic cues are most relevant to recognize emotions through cochlear implants. To do so, we used stimuli that allowed vocal and musical auditory emotions to be comparatively assessed while controlling for confounding factors. These stimuli were used to evaluate emotion perception in cochlear implant users (Experiment 1) and to investigate emotion perception in natural versus cochlear implant hearing in the same participants with a validated cochlear implant simulation approach (Experiment 2). Our results showed that vocal and musical fear was not accurately recognized by cochlear implant users. Interestingly, both experiments found that timbral acoustic cues (energy and roughness) correlate with participant ratings for both vocal and musical emotion bursts in the cochlear implant simulation condition. This suggests that specific attention should be given to these cues in the design of cochlear implant processors and rehabilitation protocols (especially energy, and roughness). For instance, music-based interventions focused on timbre could improve emotion perception and regulation, and thus improve social functioning, in children with cochlear implants during development.

The Montreal Protocol for Identification of Amusia.

The Montreal Battery for the Evaluation of Amusia (MBEA; Peretz, Champod, & Hyde Annals of the New York Academy of Sciences, 999, 58-75, 2003) is an empirically grounded quantitative tool that is widely used to identify individuals with congenital amusia. The use of such a standardized measure ensures that the individuals tested will conform to a specific neuropsychological profile, allowing for comparisons across studies and research groups. Recently, a number of researchers have published credible critiques of the usefulness of the MBEA as a diagnostic tool for amusia. Here we argue that the MBEA and its online counterpart, the AMUSIA tests (Peretz et al. Music Perception, 25, 331-343, 2008), should be considered steps in a screening process for amusia, rather than standalone diagnostic tools. The goal of this article is to present, in detailed and easily replicable format, the full protocol through which congenital amusics should be identified. In providing information that has often gone unreported in published articles, we aim to clarify the strengths and limitations of the MBEA and to make recommendations for its continued use by the research community as part of the Montreal Protocol for Identification of Amusia.

Cardiorespiratory optimization during improvised singing and toning.

We evaluated the effect of different forms of singing on cardiorespiratory physiology, and we aimed at disentangling the role of breathing from that of vocal production. Cardiorespiratory recordings were obtained from 20 healthy adults at rest and during: a) singing of familiar slow songs as in the standard form of Western culture; b) improvised vocalization of free vowel sounds, known as toning. To disentangle the role of breathing from that of vocal production, we compared the vocal conditions with matched breathing-only conditions. Toning significantly improved heart rate variability, ventilatory efficiency and slowed respiration to almost exactly six breaths per minute (p < 0.001), a pattern that is known to optimize cardiovascular function and that coincides with the period of endogenous circulatory rhythms. Singing songs also positively impacted cardiorespiratory function, although to a lesser extent. The breathing pattern imposed upon participants in the absence of vocal production was sufficient to generate the physiological benefits. The effects of toning are similar to what has been previously described as a result of engaging in formal breathing exercises. Toning and singing may offer an engaging and cost effective tool to trigger beneficial respiratory patterns and the related cardiovascular benefits.

Introduction to The neurosciences and music IV: learning and memory.

The conference entitled "The Neurosciences and Music-IV: Learning and Memory'' was held at the University of Edinburgh from June 9-12, 2011, jointly hosted by the Mariani Foundation and the Institute for Music in Human and Social Development, and involving nearly 500 international delegates. Two opening workshops, three large and vibrant poster sessions, and nine invited symposia introduced a diverse range of recent research findings and discussed current research directions. Here, the proceedings are introduced by the workshop and symposia leaders on topics including working with children, rhythm perception, language processing, cultural learning, memory, musical imagery, neural plasticity, stroke rehabilitation, autism, and amusia. The rich diversity of the interdisciplinary research presented suggests that the future of music neuroscience looks both exciting and promising, and that important implications for music rehabilitation and therapy are being discovered.

Spinal modulation of nociception by music.

Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant-stimulating, pleasant-relaxing, unpleasant-stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain-modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant-stimulating and pleasant-relaxing musical condition, indicating that the arousal of music had little influence on pain processing.

[Cerebral mechanisms involved in the interaction between pain and emotion]. / Mécanismes cérébraux impliqués dans l'interaction entre la douleur et les émotions.

INTRODUCTION: Pain is an unpleasant and intrusive sensation, warning of actual or potential tissue damage. Over the last fifteen years, functional cerebral imaging research has demonstrated the involvement of many cerebral structures in the experience of pain. BACKGROUND: Intimately linked to the notion of suffering, the affective dimension of pain relies on neurophysiological systems partly distinct anatomically from those involved more specifically in its sensory dimension. Some pathways convey nociceptive information to the somatosensory cortex and the insula, contributing to the sensory aspects of pain (e.g.: sensory intensity), and secondarily, to its affective dimension. Other pathways project directly to the anterior cingulate cortex, the insula, the amygdala and to the prefrontal cortices, which are structures involved in the affective dimension of pain (unpleasantness of pain and regulation of autonomic and behavioral responses). Interestingly, these latter regions are an integral part of the cerebral emotional networks. PERSPECTIVES AND CONCLUSION: This close anatomical relationship between pain and emotions circuits could explain the powerful emotional impact of pain as well as the reciprocal modulatory effect of emotions on pain observed in clinical and experimental studies. More specifically, this modulatory effect might reflect interactions between emotional and nociceptive systems in the prefrontal and cingulate cortices, ventral striatum, amygdala and hippocampal regions. Taken together, these observations further attest to the emotional nature of pain experience.

Are text and tune of familiar songs separable by brain damage?

The recognition of text and tune in songs was examined in a music-agnosic patient and five matched controls. Listeners had to focus on one component of the song at a time (text or music) and had to decide whether the component was familiar or unfamiliar. Songs were either matched (i.e., an original familiar or an original unfamiliar song) or mismatched (a combination of a familiar component with an unfamiliar one). Normal listeners displayed response patterns that are congruent with those obtained previously in different experimental settings and which showed that text and tune are difficult to separate. Data collected in the patient, however, suggest some independence between text and music in songs. Moreover, the usual asymmetry in favor of text was much reduced when later verses were used. Overall, the results are interpreted as revealing strong association, not integration, between the musical and the verbal component of familiar songs.

Brain specialization for music. New evidence from congenital amusia.

Brain specialization for music refers to the possibility that the human brain is equipped with neural networks that are dedicated to the processing of music. Finding support for the existence of such music-specific networks suggests that music may have biological roots. Conversely, the discovery that music may have systematic associations with other cognitive domains or variable brain organization across individuals supports the view that music is a cultural artifact. Currently, the evidence favors the biological perspective. There are numerous behavioral indications that music-specific networks are isolable in the brain. These neuropsychological observations are briefly reviewed here with special emphasis on a new condition, that of congenital amusia (also commonly referred to as tone deafness).

Cortical deafness to dissonance.

Ordinary listeners, including infants, easily distinguish consonant from dissonant pitch combinations and consider the former more pleasant than the latter. The preference for consonance over dissonance was tested in a patient, I.R., who suffers from music perception and memory disorders as a result of bilateral lesions to the auditory cortex. In Experiment 1, I.R. was found to be unable to distinguish consonant from dissonant versions of musical excerpts taken from the classical repertoire by rating their pleasantness. I.R.'s indifference to dissonance was not due to a loss of all affective responses to music, however, since she rated the same excerpts as happy or sad, as normal controls do. In Experiment 2, I.R.'s lack of responsiveness to varying degrees of dissonance was replicated with chord sequences which had been used in a previous study using PET, in examining emotional responses to dissonance. A CT scan of I.R.'s brain was co-registered with the PET activation data from normal volunteers. Comparison of I.R.'s scan with the PET data revealed that the damaged areas overlapped with the regions identified to be involved in the perceptual analysis of the musical input, but not with the paralimbic regions involved in affective responses. Taken together, the findings suggest that dissonance may be computed bilaterally in the superior temporal gyri by specialized mechanisms prior to its emotional interpretation.

A developmental study of the affective value of tempo and mode in music.

Do children use the same properties as adults in determining whether music sounds happy or sad? We addressed this question with a set of 32 excerpts (16 happy and 16 sad) taken from pre-existing music. The tempo (i.e. the number of beats per minute) and the mode (i.e. the specific subset of pitches used to write a given musical excerpt) of these excerpts were modified independently and jointly in order to measure their effects on happy-sad judgments. Adults and children from 3 to 8 years old were required to judge whether the excerpts were happy or sad. The results show that as adults, 6--8-year-old children are affected by mode and tempo manipulations. In contrast, 5-year-olds' responses are only affected by a change of tempo. The youngest children (3--4-year-olds) failed to distinguish the happy from the sad tone of the music above chance. The results indicate that tempo is mastered earlier than mode to infer the emotional tone conveyed by music.

Education, age, and the Brown-Peterson technique.

In this article, we discuss the effects of education level and age on short-term memory. The performance of young and elderly persons was compared on an adapted version of the Brown-Peterson procedure. Participants were asked to report consonant trigrams, after variable time periods, during which they performed a mental addition task or an articulation task. A control condition consisted of a no-interference task. Both age groups were divided according to individual educational level (greater or less than the median number of school years in each age group). The results revealed a significant effect of education. Moreover, the education effect interacted with the task: participants with less education were more impaired in mental addition than in articulation. However, neither the age effect nor the interactions involving age reached significance. These results indicate that education, to a greater extent than age, should be considered a determining factor of performance when interpolated tasks of high demand are used with the Brown-Peterson procedure.

Divided attention between lyrics and tunes of operatic songs: evidence for independent processing.

Excerpts from French operatic songs were used to evaluate the extent to which language and music compete for processing resources. Do these two dimensions conflict? Are they integrated into a single percept? Or are they independent? The final word of each excerpt was either semantically congruous or incongruous relative to the prior linguistic context and was sung either in or out of key. Participants were asked to detect either the semantic or the melodic incongruity (single task) or both (dual task). We predicted a dual-task deficit if these tasks conflicted and no deficit if they were either independent or integrated. In order to distinguish between these last two outcomes, trial-by-trial contingency analyses were also computed, predicting no correlation if the tasks were conflicting or independent, a positive correlation under the assumption of integration and a negative correlation if dividing attention is impossible. Our results show similar levels of performance in single and dual tasks and no correlation between dual-task judgments, thus suggesting that semantic and melodic aspects of language are processed by independent systems. In addition, a comparison between musicians and nonmusicians shows that these conclusions are independent of musical expertise.

Local and global processing of music in high-functioning persons with autism: beyond central coherence?

A multi-modal abnormality in the integration of parts and whole has been proposed to account for a bias toward local stimuli in individuals with autism (Frith, 1989; Mottron & Belleville, 1993). In the current experiment, we examined the utility of hierarchical models in characterising musical information processing in autistic individuals. Participants were 13 high-functioning individuals with autism and 13 individuals of normal intelligence matched on chronological age, nonverbal IQ, and laterality, and without musical experience. The task consisted of same-different judgements of pairs of melodies. Differential local and global processing was assessed by manipulating the level, local or global, at which modifications occurred. No deficit was found in the two measures of global processing. In contrast, the clinical group performed better than the comparison group in the detection of change in nontransposed, contour-preserved melodies that tap local processing. These findings confirm the existence of a "local bias" in music perception in individuals with autism, but challenge the notion that it is accounted for by a deficit in global music processing. The present study suggests that enhanced processing of elementary physical properties of incoming stimuli, as found previously in the visual modality, may also exist in the auditory modality.

Patterns of music agnosia associated with middle cerebral artery infarcts.

The objective of the study is to evaluate if the rupture of an aneurysm located on the middle cerebral artery (MCA) results in disorders of music recognition. To this aim, 20 patients having undergone brain surgery for the clipping of a unilateral left (LBS), right (RBS) or bilateral (BBS) aneurysm(s) of the MCA and 20 neurologically intact control subjects (NC) were evaluated with a series of tests assessing most of the abilities involved in music recognition. In general, the study shows that a ruptured aneurysm on the MCA that is repaired by brain surgery is very likely to produce deficits in the auditory processing of music. The incidence of such a deficit was not only very high but also selective. The results show that the LBS group was more impaired than the NC group in all three tasks involving musical long-term memory. The study also uncovered two new cases of apperceptive agnosia for music. These two patients (N.R. and R.C.) were diagnosed as such because both exhibit a clear deficit in each of the three music memory tasks and both are impaired in all discrimination tests involving musical perception. Interestingly, the lesions overlap in the right superior temporal lobe and in the right insula, making the two new cases very similar to an earlier case report. Altogether, the results are also consistent with the view that apperceptive agnosia results from damage to right hemispheric structures while associative agnosia results from damage to the left hemisphere.

Laterality effects in processing tonal and atonal melodies with affective and nonaffective task instructions.

Right-handed university subjects were presented with monaural melodies that either conformed to the rules of the Western tonal system (tonal melodies) or that systematically deviated from it (atonal melodies) while containing similar contours and pitch skips. Subjects were tested under two different task instructions. One group was requested to judge whether each melody sounded correct or not (the nonaffective task); the other group had to judge whether each melody sounded pleasant or not (the affective task). The nonaffective task was found to elicit essentially no ear difference. In contrast, the affective instruction induced opposite and reliable laterality effects, depending on the valence of the response. The pleasant responses were indicative of a left hemisphere predominance and the unpleasant responses of a right hemisphere predominance. The results are consistent with the claim that the left hemisphere is biased toward positive emotions and the right to negative emotions. Moreover, the results suggest that affective appreciation of melodies is dissociable from their nonaffective judgment.

Frontal processing and auditory perception.

Disordered processing of the pattern in sound over time has been observed in a number of clinical disorders, including developmental dyslexia. This study addresses the brain mechanisms required for the perception of such a pattern. We report the systematic evaluation of temporal perception in a patient with a single intact right auditory cortex and a large right frontal lobe lesion. A striking dissociated deficit was demonstrated in the perception of temporal pattern at the level of tens or hundreds of milliseconds. This proves that, contrary to common belief, mechanisms in the pathway up to and including the primary auditory cortex are not sufficient for the normal perception of temporal pattern. This work suggests a need for frontal processing for the normal perception of auditory pattern.