SIRS Research Stories

Treatment resistance in schizophrenia is a major clinical problem with one third of schizophrenia patients showing non-response to standard antipsychotic treatment. The delay in identifying these patients leads to prolonged ineffective treatment, longer hospitalization, unnecessary side effects and lower quality of life for those individuals. There is an urgent need for (bio)markers that can identify treatment-resistant patients early on, enabling timely intervention and improving prognosis.

During my PhD I have developed a keen interest in the neurobiology of psychosis and its relation to treatment response in first episode psychosis. Elucidating the underlying neurobiology of treatment resistance in psychosis could aid in better treatment selection and result in markers for earlier identification of these patients. The core focus of my PhD was the development and application of the novel neuromelanin-sensitive MRI (NM-MRI) technique as a potential clinical marker for treatment resistance. Additionally, I explored alternative markers, including plasma dopa decarboxylase activity as a blood marker and alterations in neurotransmitters, including glutamate and gamma-aminobutyric acid (GABA) levels. These markers hold significance for guiding treatment decisions, particularly in considering clozapine, the antipsychotic recognized for its superior effectiveness in treatment resistant schizophrenia.

At the SIRS 2022 conference, I had the honor to receive an early career award and to present the most notable finding from my PhD including a NM-MRI study in first episode psychosis patients. NM-MRI is a novel non-invasive MRI technique that indirectly measures dopamine functioning. In psychosis research, a common method for evaluating dopamine functioning is [18F]F-DOPA PET imaging, which has consistently shown increased activity in specific brain areas. Interestingly, treatment resistant patients do not show this increased dopamine functioning and show levels comparable to healthy individuals. Unfortunately, [18F]FDOPA PET imaging is expensive and relatively burdensome for patients, since it uses radioactivity and is administered intravenously, making it impractical for widespread use in screening for treatment resistance. NM-MRI as a proxy of dopamine functioning presents a promising alternative due to its non-invasive nature. NM-MRI shows increased signal in schizophrenia patients compared to healthy individuals, but had not yet been tested in treatment resistant schizophrenia. We aimed to determine whether treatment resistant patients show lower NM-MRI signal compared to patients who responded to antipsychotic medication. To accomplish this, we conducted a study in first episode psychosis patients, with a baseline and 6 month follow up measurement. In line with our hypothesis, treatment resistant patients showed significantly lower NM-MRI signal compared to responders, and similar NM-MRI signal compared to healthy individuals. Furthermore, NM-MRI appeared to be relatively robust as NM-MRI signal remained stable over six months follow-up and was not associated with illness duration, medication duration or dosage. These findings provide further evidence for dopaminergic differences between treatment resistant patients and responders, and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia. This study has recently been published in the American Journal of Psychiatry and can be accessed online.

Following our findings that treatment resistant schizophrenia may be associated with a normal dopamine rather than an increased dopamine system, we redirected our attention to another neurotransmitter system: glutamate and GABA. These neurotransmitters are believed to play a role in treatment resistant schizophrenia. As a result, we aimed to further elucidate the roles of glutamate and GABA in the anterior cingulate cortex in first episode treatment resistant schizophrenia. I will present the results of this study as a poster at SIRS 2024 on Thursday.

Currently, I am a post-doctoral researcher at the Department of Psychiatry, Amsterdam UMC in the Netherlands. In this role I contribute to various projects, encompassing both neuroimaging and clinical studies in psychosis. Moving forward, I plan to expand my research endeavors while continuing to lend my expertise to other projects. Over the coming years, my goal is to deepen my understanding and experience in the field of psychosis. Eventually I want to use my accumulated expertise to pursue grants and establish my own research program dedicated to improving diagnostics and treatment for early psychosis.

My first contact with brain research was already in school in biology classes. The complex biology of the brain functioning was fascinating to me because of it’s many mysteries. When deciding what to study I always wanted to do research but also wanted to work on something that is directly related to people’s lives. The challenges in medicine seemed to fit these requirements. During my first internships I was intrigued by psychiatry and schizophrenia research. There were so many open questions and riddles to solve. So I started to do brain research at the Max-Planck Institute for Cognitive and Brain Sciences in Leipzig and then started my clinical career at Charité Berlin focusing on brain research in Schizophrenia. During my clinical routine I was fascinated by the extraordinary powers and abilities patients have. Although behavior sometimes is described as "non-functional" there is an enormous creativity and resilience in people with mental disorders. The multifactorial origins of those disorders have long puzzled researchers and clinicians alike. It’s multifaceted nature presents a significant challenge, but also an opportunity for innovation and discovery.

When I started my career, I embarked on a journey to unravel the intricacies of schizophrenia. I started with cutting-edge imaging technology and the goal for better understanding the human brain during crisis.  Neuroimaging techniques have revolutionized our ability to explore the complexities of the brain. Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and Functional MRI (fMRI) allow us to visualize the structure, function, and connectivity of neural circuits with unprecedented detail. These tools offer invaluable insights into the pathophysiology. I focused on alterations in glutamatergic and dopaminergic brain functioning, however, I was not completely satisfied and felt that despite decades of research, the underlying neurobiological mechanisms remain elusive, making diagnosis and treatment such a challenging task. I then delve more into the complex interaction of environmental factors and psychotic experiences. And landed in digital health to support patients in outpatient setting with innovative and effective tools. In addition to advancing our understanding of schizophrenia, technology has also revolutionized the way we support and empower patients. Digital tools and mobile applications have emerged as valuable adjuncts to traditional therapeutic approaches. These tools offer a wide range of functionalities, including symptom tracking, medication management, activation of resources and psychoeducation. One of the most significant advantages of digital tools is their ability to tailor interventions to the individual needs of patients. While the integration of digital tools into schizophrenia care holds immense promise, it is not without its challenges. Issues such as data privacy, accessibility, and the digital divide must be carefully addressed to ensure equitable access to these resources. Additionally, ongoing research is needed to validate the efficacy of these interventions and optimize their usability in clinical settings. In conclusion, the intersection of neuroimaging research and digital technology offers unprecedented opportunities to advance our understanding of schizophrenia and transform patient care. By embracing innovation and collaboration, we can navigate the challenges ahead and continue to support and empower patients during their recovery. While working in the field of schizophrenia research fostering interdisciplinary collaboration is what I enjoyed the most. 

I began studying genetics in my first year at Harvard, somewhat by accident. I had applied to be part of a seminar entitled “Chess and Mathematics,” but that course was filled, and I was bumped into “Darwin’s Finches”. I was disappointed, but not for long. I began to spend time in the archives of the Museum of Natural History, measuring the beaks of finches collected nearly 200 years ago, each with a tag tied to its leg with minute handwriting denoting the bird’s scientific name. Holding the birds that inspired the theory of evolution was the start of my fascination with genetics and classification. The next semester I moved to a synthetic biology wet lab, and after that to a drosophila lab at the Fred Hutchinson Cancer Research Center. At the same time, I was developing an interest in psychiatry and clinical psychology. My grandfather, who I idolized, was a psychiatrist. His son, who I never met, was diagnosed with schizophrenia. The family was unusually tight-knit, so my uncle’s absence was conspicuous, and highlighted how profoundly schizophrenia had impacted my father’s family of origin.  

I pursued a doctorate in clinical psychology at the University of Iowa because it presented the opportunity to pursue genomics research and clinical training in psychopathology. At both Iowa and the Minneapolis Veterans Affairs Medical Center, I was able to spend time with individuals who had experienced psychosis, working on inpatient, partial hospitalization, and outpatient treatment settings. When a postdoctoral opportunity arose on the Suffolk County Project, led by Drs. Roman Kotov and Evelyn Bromet and currently the longest-running study of first-admission psychosis in the world, I was thrilled to merge my research and clinical interests. My work with the project has focused on understanding how genetic risk factors manifest longitudinally over the 35 years the study has been running. We have shown that genetic risk can indicate who is more likely to experience a more severe course of negative symptoms. With the leaders of other first-episode studies, we are developing a consortium of longitudinal studies that can definitively evaluate how genetic risk impacts the course of symptoms, cognition, function, and response to treatment in psychotic disorders. 

In the past two years, I have developed an arm of research that aims to leverage what we know about the structure of psychosis to improve the power and precision of psychosis GWAS. Preliminary results from these analyses have confirmed the genetic structure of psychotic symptoms, mania, and depressive symptoms mirrors phenotypic structure, such that each genetic factor is relatively independent of the other. The support of the SIRS Early Career Award allowed me to present this work at the society’s 2022 meeting. A related line of research takes a broader approach, and tests whether transdiagnostic phenotypes of internalizing, externalizing, and psychosis, can identify more genetic risk factors than case-control GWAS. My hope is that this line of research will provide a clearer picture of psychotic disorders and the genetic risk factors associated with them, to facilitate the development of better diagnostic tools and treatments. 

My name is Théo KORCHIA, and I am a French psychiatrist, particularly involved in the treatment of early-onset schizophrenic disorders. 

First of all, I'd like to thank the Schizophrenia International Research Society for honouring me with this prestigious award, as well as the Faculty of Medical and Paramedical Sciences at Aix-Marseille University (France) and the Assistance Publique des Hôpitaux de Marseille (APHM), which supported me and enabled me to spend a year at McGill University in Montreal. 

Schizophrenia is a pathology often shrouded in mystery and prejudice, which profoundly affects the lives not only of those who suffer from it, but also those around them. 

Management of the first psychotic episodes determines the outcome and prognosis of patients, and it is therefore necessary to improve it. Generally speaking, my work highlights the value of pharmacogenetics, adapting and personalizing the antipsychotic treatment to different genetic profiles for greater efficacy. Consequently, various side-effects of antipsychotic therapy, notably sexual dysfunction which is very disabling and leads to discontinuation of treatment, are drastically reduced. Patient motivation must also be strengthened by including them in therapeutic decisions to improve overall quality of life. 

A particularly innovative aspect of my work concerns the impact of sexual dysfunction in patients suffering from schizophrenia. This issue, which has long remained on the fringes of psychiatric research, is crucial to patients' quality of life. Sexual dysfunction can be both a symptom of the illness and a side-effect of treatment, making it a dual challenge to overcome. 

My perseverance on this issue has led to the publication of a meta-analysis of over 21,000 patients worldwide, in the journal JAMA Psychiatry. 

Our study reveals with edifying clarity the high frequency of sexual dysfunction in individuals with schizophrenia spectrum disorders, showing an overall prevalence of 56.4%, with great variation in the types of dysfunction. This underlines the urgency of no longer neglecting adverse sexual effects in the treatment of schizophrenia. In the same way that weight gain or somnolence are side-effects commonly considered in the evaluation of antipsychotic treatments, it is crucial to include sexual dysfunction in our benefit-risk analysis. Recognizing and addressing these adverse effects goes beyond improving patients' quality of life; it represents a significant step forward in establishing a solid therapeutic alliance. Open communication about these issues, which are often stigmatized or played down, fosters a relationship of trust between doctor and patient, which is essential for effective management of schizophrenia. By taking these undesirable effects into account, we are improving not only adherence to treatment, but also the overall management of the patient, by recognising the importance of sexual health as a fundamental component of the patient's well-being. 

This study therefore represents a significant advance, opening-up new prospects for treatments that are more respectful and tailored to patients' needs. 

What drives my research is the conviction that innovation in psychiatry is not limited to the discovery of new drugs. It also lies in our ability to rethink the way we treat patients, by integrating dimensions of their experience that have been underestimated until now. The aim is twofold: to improve the quality of life of people suffering from schizophrenia and to reduce the obstacles to effective treatment, particularly those associated with the side effects of medication. 

The implications of the studies I lead aim to have a direct impact on clinical practice by providing healthcare professionals with the tools they need to build a solid therapeutic alliance, thereby encouraging adherence to treatment and improving clinical outcomes. Considering sexual dysfunction, and more broadly the side effects of antipsychotics, is a concrete example of this influence. 

My vision is of a dynamic psychiatry that is constantly evolving, where care is tailored to the uniqueness of each individual, and where each scientific advance lights the way towards better mental health. 

I am therefore grateful to be able to share with you not only my research objectives, but also my vision of a future in which the management of schizophrenia is more enlightened, more effective and, above all, more humane. The road is long, the challenges many, but the passion that drives my quest is unshakeable. With determination and perseverance, we can provide meaningful answers to those struggling with mental suffering, and open up new horizons for the psychiatry of tomorrow. 

Hyeon-Seung Lee

Individuals with depression often report their core belief of "I am worthless and unlovable." Individuals with anxiety disorders and OCD often report “what if” statement as a sign of excessive worry that leads to the thoughts of the worst-case scenario. Then, what would be a representative sign of schizophrenia? It is difficult to pick just one phenomenon given the multifaceted nature of the disorder, but I would pick "as if" statements related to the sense of self. Past research points out that self-disturbances are intertwined with the emergence of schizophrenia symptoms such as delusions and hallucinations. People at-risk often describe their experiences like this: “It feels 'as if' I am untuned to my body.” The anomalous feeling of altered self (agency, body ownership, self-boundary, and the experience of sensation, perception, and emotion) is a salient feature in the lives of those with schizophrenia. Bleuler’s original conceptualization of schizophrenia as that of the splitting of the mind and Kraepelin’s analogy of “an orchestra without a conductor” that indicates “a loss of inner unity”, both emphasize aberrations in the basic sense of self.  These self-disturbances have been shown to be important for predicting functional outcomes.  

Although the Research Domain Criteria (RDoC) of the National Institute of Mental Health (NIMH) and the International Classification of Diseases (ICD-11) include self-related features, self-disorder is not a prominent feature in either approach. Moreover, the sense of self has been ignored in the diagnosis, research, and treatment of schizophrenia due to lack of reliable and valid measures. With new methodological advances, it is now possible to empirically investigate the etiology and nature of self-disorders. As an early career researcher working with Dr. Sohee Park and multidisciplinary collaborators, I have developed and implemented novel experimental paradigms to elucidate and measure aspects of self-disturbances in schizophrenia. For instance, I have used virtual reality (VR) based measures to assess the neurocognitive representation of bodily space (i.e., peripersonal space) and how it is linked to schizophrenia symptoms. I also utilized VR-based social skills training to provide simulation and rehearsal of interpersonal interactions in realistic settings rather than explicitly teaching social cognitive skills to individuals with schizophrenia. In addition, I use computerized tools to visualize embodied emotions, manipulate cortical activities with brain stimulation, and assess the integrity of frontoparietal networks with neuroimaging to fully investigate the self-disturbances, symptoms, and social dysfunctions in schizophrenia. 

Specifically, my master’s thesis focused on the abnormal spatial self-consciousness in schizophrenia formed through multisensory processing. As objects or people approach one’s personal space, multisensory neurons in the frontoparietal brain facilitate appropriate reactions. I used VR-based multisensory integration tasks to identify the inflection point where multisensory reaction time is facilitated, which estimates the size and slope of personal space. I found that individuals with schizophrenia generate small but unclearly-defined personal space boundaries relative to controls in the social context. The size or shape of personal space was associated with the severity of negative symptoms and hallucinations. In an ongoing review study, I further demonstrated how personal space is altered in various mental disorders (e.g., anxiety, post-traumatic stress disorder, autism spectrum disorders, etc.). The personal space size is enlarged in various disorders; however, the self-space is more solidly formed in individuals with anxiety and autism spectrum disorders, while the boundary is unclearly generated in those with schizophrenia. My dissertation research further examines the altered representation of personal space, investigating the effect of threat, social distress, and socioemotional factors. 

Another line of research is investigating cross-cultural differences in the manifestation of psychosocial dysfunction. Previously, I examined the impact of the COVID-19 pandemic on the mental health of the general population from various cultures. Given the pandemic and social distancing were increasing feelings of social disconnection and loneliness, I expected that social disconnection and loneliness play a major role in poor physical and mental health. Delving into how cultural differences in public health strategies and compliance of the general population yield variances in reported stress, mood, anxiety, and psychotic experiences provided me with either a microscopic or a macroscopic view of psychosocial dysfunction. Moreover, I investigated culture-general and specific aspects of mental health symptoms and abnormal self-related experiences in schizophrenia. Previous cross-cultural works highlighted that though symptoms and self-disturbances are salient and prevalent in both Western and non-western cultures, there were culture-specific aspects such as relatively high tolerance for anomalous self-experiences and less attenuated embodied emotion in Koreans. I would like to continue to investigate cultural effects on psychosocial functions. 

Psychiatric research is still mostly driven by researchers from Europe and North America. As a Korean scientist, I believe we have valuable contributions to make to this field and I hope to increase the representation of Korean and other Asian scientists in the field of schizophrenia research. Increased diversity of ideas and approaches will surely positively impact the future of the Schizophrenia International Research Society (SIRS). 

Kirsten Borup Bojesen, MD, PhD 

Residency trainee in psychiatry, postdoctoral researcher 

Copenhagen University Hospital, Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Center Glostrup, Nordstjernevej 41, 2600 Glostrup 

As a clinician-scientist, I have been struck by the large proportion of patients with schizophrenia insufficiently treated with antipsychotics and by the negative impact of cognitive deficits on everyday life. This has inspired me to explore the neurotransmitter aberrations underlying insufficient treatment response and cognitive deficits in patients with psychosis with a key focus on glutamate and GABA. My hope is that research on the impact of glutamatergic and GABAergic neurotransmitter disturbances on insufficient treatment outcome and cognition can pave the way for development of novel therapeutics.  

My research has focused on glutamatergic and GABAergic aberrations in initially antipsychotic-naïve patients with first-episode psychosis and the impact of these disturbances on short- and long-term treatment outcome as well as cognitive performance. Specifically, we have found that higher levels of glutamate in thalamus and lower levels of GABA in dorsal Anterior Cingulate Cortex (dACC) are present from illness onset in antipsychotic-naïve first-episode patients and related to poor short-term treatment outcome after 6 and 26 weeks. Moreover, low GABA levels in dACC at illness onset are associated with poor functional outcome after two years of illness, and lower levels of glutamate in the dACC are associated with impaired cognitive function. Going further into the neurobiological underpinnings of insufficient treatment response, we investigated if brain glutamate and GABA levels were related to striatal dopaminergic function that is the main target of antipsychotic compounds. We observed that lower GABA levels in dACC were associated with higher striatal perfusion during the first two years of illness, suggesting that prefrontal GABA levels have a downregulatory effect on striatal activity and may be a novel treatment target. Furthermore, an aberrant interrelation between dACC levels of GABA and dopamine synthesis capacity in nucleus accumbens assessed with positron emission tomography could identify antipsychotic-naïve patients from healthy controls, whereas individual neurotransmitters were unable to do so, suggesting that aberrant interactions between neurotransmitters are more crucial for development of schizophrenia than single neurotransmitter disturbances. Currently, we examine the trajectory of glutamate levels in dACC and thalamus during the first two years of illness and relate neurotransmitter levels to long-term treatment outcome and cognitive function. Moreover, we investigate if a glutamatergic compound developed for neurological disorders is effective in patients with first-episode psychosis.   

Our findings so far imply that treatment targeting glutamatergic and GABAergic disturbances can be beneficial in first-episode patients during the first two years of illness. As novel treatments are warranted not only during first-episode psychosis but also in the more chronic stage of the illness, we are currently preparing to re-examine brain levels of glutamate and GABA in the same cohort of patients and healthy controls after ten years.  

I am always thrilled to attend the SIRS conference and get inspirated by both junior and senior researchers dedicating their time to improve the treatment and everyday life for patients with schizophrenia and psychotic disorders. The SIRS early career award 2023 and mentor program was very helpful in expanding my international network, and I especially gained from guidance on funding, publishing strategies, and life-work balance in academia. The program has supported me in developing my research career trajectory. It makes me believe that our combined international effort into unravelling the neurobiological and environmental factors underlying schizophrenia will lead to development of novel treatment options during the next decades. 

By: Dr. Natalia Mansur Haddad

I have enjoyed studying and understanding schizophrenia since the initial period of my first graduation, still in the field of psychology. Afterwards, I went to medical school to become a psychiatrist. Thereby, I have always been fascinated by psychosis in general as an area of ​​study and research. During the last 10 years of clinical practice, I delved deeper into the care of chemically dependent patients and substance use disorders. At the confluence of these subjects, I have the privilege of studying the endocannabinoid system in a population with psychosis and how the impact of cannabis can influence its regulation. 

In 2022 I had the great opportunity to win the SIRS Early Career Award. On that occasion, I was able to show the partial results of our study, which pointed to the use of cannabis as a factor that influences the reduction in endocannabinoid 2-AG values ​​in plasma. In the following years, we continued to study the ECS and found an increase in peripheral CB2 receptors associated with the use of non-clozapine antipsychotics. The data complement the current literature, which is ambiguous and should be further studied. 

 It was very important for a young investigator like me to attend to an international meeting and it was a unique opportunity to establish international collaboration with important researchers in the field. It was a great honor and an encouragement to proceed with my research. I recently published an article with the findings of my thesis on changes in the endocannabinoid system of patients with schizophrenia in the European Archives of Psychiatry and Clinical Neuroscience Journal. 

I have started my master's degree in February 2020, upgraded to doctorate degree and my thesis defense will take place next month.
All this development and career evolution in recent years gives me confidence to continue researching and sharing the results of my research with the international community. I believe that one of the main objectives is to align research results with clinical practice, thus contributing to the development of new screening methods for the disorder such as biomarkers, which can improve the diagnosis, treatment and prognosis of these individuals. 

My research group is very diverse, we work at a Public Hospital and University in São Paulo - Brazil, and adverse situations are very frequent in an underrepresented country. However, year after year we prove that we can carry out quality research and talk to researchers from around the world, contributing relevant data from a large and diverse population sample with a major impact on global health. We intend to continue building knowledge and strengthening ties with the international community. 

Humans are innately social beings and, in almost all cultures, vocal communication is the dominant mode for social interactions. It is, therefore, not surprising that voices became the most salient auditory signal. We often use voices to communicate verbal information but voices are much more than that: they convey a wealth of socially relevant information about the speaker (e.g., age, sex, emotional state, social traits), which can be decoded from the briefest of utterances. Voices are, therefore, fundamental for social experience.

My research is focused on understanding how humans make sense of and use vocal information to communicate with each other. I am particularly interested in how these mechanisms, when altered, may explain the characteristic symptoms of schizophrenia, such as auditory verbal hallucinations. The investigation of language and communication in schizophrenia during my PhD convince me of the importance of looking at voice perception mechanisms to understand the experience of hearing voices without matching external acoustic input. I pursued the investigation of these mechanisms during my Post-Doctoral studies at Harvard Medical School, and later as director of the Voice, Emotion & Speech Laboratory at the University of Lisbon.

Auditory verbal hallucinations remain one of the most puzzling phenomena of human experience: they are self-generated but are typically experienced as a form of communication from another (or other) speaker(s). They are one of the most troubling symptoms in psychosis and thus contribute to significant suffering. However, hallucinations may also be reported in the general population without need for psychiatric care. Despite many efforts to explain this puzzling phenomenon, the underlying pathophysiology is still poorly understood. My studies suggest that auditory verbal hallucinations co-opt the neurocognitive mechanisms underpinning voice generation and perception. For example, we documented disrupted voice feedback processing in both adult psychotic patients and nonclinical voice hearers, which may link to dysfunctional cerebellar circuitry. Based on these findings, we put forward a framework that accentuates the role of the cerebellum in voice feedback processing and auditory verbal hallucinations. These findings add to prior studies showing that predictive processing dysfunction is at the basis of auditory verbal hallucinations. We also showed that hallucination proneness is associated with hypersalient responses in voice-sensitive regions of the cerebral cortex to acoustic features coding speaker identity.

Auditory verbal hallucinations are associated with greater risk of conversion to psychosis compared to other types of hallucinations, contribute transdiagnostically to psychopathology in adolescents, and predict poor functional outcome in schizophrenia. Detecting early alterations at the neurophysiological or behavioral levels before the development of full-blown psychotic symptoms could radically modify the risk trajectory. Voice processing could be a strong candidate for differentiating between vulnerability, risk, and clinical profiles. This is an innovative concept and of high relevance as voice-sensitive tasks are relatively cheap and reliable measures that could be implemented in larger samples with a longitudinal outlook. Our ongoing studies are testing this hypothesis.

This work has been a collaborative effort and I have been extremely lucky to have found brilliant mentors who continue to inspire me, including Margaret Niznikiewicz or Sonja Kotz. I am also deeply grateful for all the learning and collaboration opportunities I have found as a SIRS member since early in my graduate training, and especially honored to have received the 2022 SIRS Rising Star Award.

My ongoing studies continue the quest for a mechanistic understanding of auditory verbal hallucinations aiming to inform future preventive strategies. Investigating vocal communication might prove especially informative to clarify why hallucinated voices are typically experienced as social entities and why they may acquire an emotional quality.