Male brain processing of the body odor of ovulating women compared to that of pregnant women.

Female chemical signals underlie the advertising of sexual receptivity and fertility. Whether the body odor of a pregnant woman also has a signaling function with respect to male behavior is yet to be conclusively established. This study examines how the body odors of ovulating and pregnant women differentially affect the behavior of heterosexual men. Body odor samples were collected from 5 pregnant women and 5 matched controls during ovulation. In a double-blind functional magnetic resonance imaging design, 18 heterosexual men were exposed to female body odors during ovulation (OV) and pregnancy (PRG) while being required to indicate the attractiveness of concurrently presented female portrait images. The participants were also required to indicate whether they assumed a depicted woman was pregnant. While neither OV nor PRG altered the perceived attractiveness of a presented face, the men tended to identify the women as pregnant while exposed to a PRG body odor. On the neural level, OV activated a network of the frontotemporal and limbic regions, while PRG activated the superior medial frontal gyrus. The results suggest that the detection of sexual availability activates the male brain regions associated with face processing and reward/motivation, whereas sensing pregnancy activates a region responsible for empathy and prosocial behavior. Thus, the female body odor during pregnancy likely helps foster circumstances conducive to the future care of offspring while the body odor advertising sexual availability promotes mating behavior. The brains of heterosexual men may be capable of unconsciously discriminating between these two types of olfactory stimuli.

Prefrontal Control Over Occipital Responses to Crossmodal Overlap Varies Across the Congruency Spectrum.

While matched crossmodal information is known to facilitate object recognition, it is unclear how our perceptual systems encode the more gradual congruency variations that occur in our natural environment. Combining visual objects with odor mixtures to create a gradual increase in semantic object overlap, we demonstrate high behavioral acuity to linear variations of olfactory-visual overlap in a healthy adult population. This effect was paralleled by a linear increase in cortical activation at the intersection of occipital fusiform and lingual gyri, indicating linear encoding of crossmodal semantic overlap in visual object recognition networks. Effective connectivity analyses revealed that this integration of olfactory and visual information was achieved by direct information exchange between olfactory and visual areas. In addition, a parallel pathway through the superior frontal gyrus was increasingly recruited towards the most ambiguous stimuli. These findings demonstrate that cortical structures involved in object formation are inherently crossmodal and encode sensory overlap in a linear manner. The results further demonstrate that prefrontal control of these processes is likely required for ambiguous stimulus combinations, a fact of high ecological relevance that may be inappropriately captured by common task designs juxtaposing congruency and incongruency.

Behavioral and neural correlates to multisensory detection of sick humans.

Throughout human evolution, infectious diseases have been a primary cause of death. Detection of subtle cues indicating sickness and avoidance of sick conspecifics would therefore be an adaptive way of coping with an environment fraught with pathogens. This study determines how humans perceive and integrate early cues of sickness in conspecifics sampled just hours after the induction of immune system activation, and the underlying neural mechanisms for this detection. In a double-blind placebo-controlled crossover design, the immune system in 22 sample donors was transiently activated with an endotoxin injection [lipopolysaccharide (LPS)]. Facial photographs and body odor samples were taken from the same donors when "sick" (LPS-injected) and when "healthy" (saline-injected) and subsequently were presented to a separate group of participants (n = 30) who rated their liking of the presented person during fMRI scanning. Faces were less socially desirable when sick, and sick body odors tended to lower liking of the faces. Sickness status presented by odor and facial photograph resulted in increased neural activation of odor- and face-perception networks, respectively. A superadditive effect of olfactory-visual integration of sickness cues was found in the intraparietal sulcus, which was functionally connected to core areas of multisensory integration in the superior temporal sulcus and orbitofrontal cortex. Taken together, the results outline a disease-avoidance model in which neural mechanisms involved in the detection of disease cues and multisensory integration are vital parts.

Audio-visual and olfactory-visual integration in healthy participants and subjects with autism spectrum disorder.

The human capacity to integrate sensory signals has been investigated with respect to different sensory modalities. A common denominator of the neural network underlying the integration of sensory clues has yet to be identified. Additionally, brain imaging data from patients with autism spectrum disorder (ASD) do not cover disparities in neuronal sensory processing. In this fMRI study, we compared the underlying neural networks of both olfactory-visual and auditory-visual integration in patients with ASD and a group of matched healthy participants. The aim was to disentangle sensory-specific networks so as to derive a potential (amodal) common source of multisensory integration (MSI) and to investigate differences in brain networks with sensory processing in individuals with ASD. In both groups, similar neural networks were found to be involved in the olfactory-visual and auditory-visual integration processes, including the primary visual cortex, the inferior parietal sulcus (IPS), and the medial and inferior frontal cortices. Amygdala activation was observed specifically during olfactory-visual integration, with superior temporal activation having been seen during auditory-visual integration. A dynamic causal modeling analysis revealed a nonlinear top-down IPS modulation of the connection between the respective primary sensory regions in both experimental conditions and in both groups. Thus, we demonstrate that MSI has shared neural sources across olfactory-visual and audio-visual stimulation in patients and controls. The enhanced recruitment of the IPS to modulate changes between areas is relevant to sensory perception. Our results also indicate that, with respect to MSI processing, adults with ASD do not significantly differ from their healthy counterparts.

Externalization Errors of Olfactory Source Monitoring in Healthy Controls-An fMRI Study.

Using a combined approach of functional magnetic resonance imaging (fMRI) and noninvasive brain stimulation (transcranial direct current stimulation [tDCS]), the present study investigated source memory and its link to mental imagery in the olfactory domain, as well as in the auditory domain. Source memory refers to the knowledge of the origin of mental experiences, differentiating events that have occurred and memories of imagined events. Because of a confusion between internally generated and externally perceived information, patients that are prone to hallucinations show decreased source memory accuracy; also, vivid mental imagery can lead to similar results in healthy controls. We tested source memory following cathodal tDCS stimulation using a mental imagery task, which required participants to perceive or imagine a set of the same olfactory and auditory stimuli during fMRI. The supplementary motor area (SMA) is involved in mental imagery across different modalities and potentially linked to source memory. Therefore, we attempted to modulate participants' SMA activation before entering the scanner using tDCS to influence source memory accuracy in healthy participants. Our results showed the same source memory accuracy between the olfactory and auditory modalities with no effects of stimulation. Finally, we found SMA's subregions differentially involved in olfactory and auditory imagery, with activation of dorsal SMA correlated with auditory source memory.

Emotional expressions of the sick face.

To handle the substantial threat posed by infectious diseases, behaviors that promote avoidance of contagion are crucial. Based on the fact that sickness depresses mood and that emotional expressions reveal inner states of individuals to others, which in turn affect approach/avoidance behaviors, we hypothesized that facial expressions of emotion may play a role in sickness detection. Using an experimental model of sickness, 22 volunteers were intravenously injected with either endotoxin (lipopolysaccharide; 2 ng/kg body weight) and placebo using a randomized cross-over design. The volunteers were two hours later asked to keep a relaxed expression on their face while their facial photograph was taken. To assess the emotional expression of the sick face, 49 participants were recruited and were asked to rate the emotional expression of the facial photographs of the volunteers when sick and when healthy. Our results indicate that the emotional expression of faces changed two hours after being made temporarily sick by an endotoxin injection. Sick faces were perceived as more sick/less healthy, but also as expressing more negative emotions, such as sadness and disgust, and less happiness and surprise. The emotional expressions mediated 59.1% of the treatment-dependent change in rated health. The inclusion of physical features associated with emotional expressions to the mediation analysis supported these results. We conclude that emotional expressions may contribute to detection and avoidance of infectious individuals and thereby be part of a behavioral defense against disease.

Sleep during naturally occurring respiratory infections: A pilot study.

There is strong experimental support that infections increase the drive for sleep in animals, and it is widely believed that more sleep is part of an adaptive immune response. While respiratory infections (RI) are very prevalent in humans, there is a striking lack of systematic knowledge on how it affects sleep. We recruited 100 people, among whom 28 became sick with an RI during the study period (fulfilling criteria for influenza-like illness, ILI, or acute respiratory infection, ARI). We measured sick participants' sleep at home, both objectively (actigraphy) and subjectively (diary ratings), for one week as well as four weeks later when healthy. During the week with RI, people spent objectively longer time in bed and had a longer total sleep time compared to the healthy week. During the infection, participants also had more awakenings, but no significant differences in sleep latency or sleep efficiency. While sick, people also reported increased difficulties falling asleep, worse sleep quality, more restless sleep and more shallow sleep, while they did not report sleep to be less sufficient. Most problems occurred at the beginning of the sickness week, when symptoms were strong, and showed signs of recovery thereafter (as indicated by interactions between condition and day/night of data collection for all the 10 sleep outcomes). The degree of symptoms of RI was related to a worse sleep quality and more restless sleep, but not to any of the objective sleep outcomes or the other subjective sleep variables. Having a higher body temperature was not significantly related to any of the sleep variables. This study suggests that having a respiratory infection is associated with spending more time in bed and sleeping longer, but also with more disturbed sleep, both objectively and subjectively. This novel study should be seen as being of pilot character. There is a need for larger studies which classify pathogen type and include baseline predictors, or that manipulate sleep, in order to understand whether the sleep alterations seen during infections are adaptive and whether sleep interventions could be used to improve recovery from respiratory infections.

The intraparietal sulcus governs multisensory integration of audiovisual information based on task difficulty.

Object recognition benefits maximally from multimodal sensory input when stimulus presentation is noisy, or degraded. Whether this advantage can be attributed specifically to the extent of overlap in object-related information, or rather, to object-unspecific enhancement due to the mere presence of additional sensory stimulation, remains unclear. Further, the cortical processing differences driving increased multisensory integration (MSI) for degraded compared with clear information remain poorly understood. Here, two consecutive studies first compared behavioral benefits of audio-visual overlap of object-related information, relative to conditions where one channel carried information and the other carried noise. A hierarchical drift diffusion model indicated performance enhancement when auditory and visual object-related information was simultaneously present for degraded stimuli. A subsequent fMRI study revealed visual dominance on a behavioral and neural level for clear stimuli, while degraded stimulus processing was mainly characterized by activation of a frontoparietal multisensory network, including IPS. Connectivity analyses indicated that integration of degraded object-related information relied on IPS input, whereas clear stimuli were integrated through direct information exchange between visual and auditory sensory cortices. These results indicate that the inverse effectiveness observed for identification of degraded relative to clear objects in behavior and brain activation might be facilitated by selective recruitment of an executive cortical network which uses IPS as a relay mediating crossmodal sensory information exchange.

Neural responses to dynamic multimodal stimuli and pathology-specific impairments of social cognition in schizophrenia and depression.

BACKGROUND: Individuals with schizophrenia and people with depression both show abnormal behavioural and neural responses when perceiving and responding to emotional stimuli, but pathology-specific differences and commonalities remain mostly unclear. AIMS: To directly compare empathic responses to dynamic multimodal emotional stimuli in a group with schizophrenia and a group with depression, and to investigate their neural correlates using functional magnetic resonance imaging (fMRI). METHOD: The schizophrenia group (n = 20), the depression group (n = 24) and a control group (n = 24) were presented with portrait-shot video clips expressing emotion through three possible communication channels: facial expression, prosody and content. Participants rated their own and the actor's emotional state as an index of empathy. RESULTS: Although no group differences were found in empathy ratings, characteristic differences emerged in the fMRI activation patterns. The schizophrenia group demonstrated aberrant activation patterns during the neutral speech content condition in regions implicated in multimodal integration and formation of semantic constructs. Those in the depression group were most affected during conditions with trimodal emotional and trimodal neutral stimuli, in key regions of the mentalising network. CONCLUSIONS: Our findings reveal characteristic differences in patients with schizophrenia compared with those with depression in their cortical responses to dynamic affective stimuli. These differences indicate that impairments in responding to emotional stimuli may be caused by pathology-specific problems in social cognition.

The influence of the COMT Val158Met polymorphism on prefrontal TDCS effects on aggression.

Increasing dorsolateral prefrontal cortex (DLPFC) activity by anodal transcranial direct current stimulation (tDCS) enhances cognitive control and might reduce aggression. The Val158Met polymorphism within the catechol-O-methyltransferase gene (rs4680) plays a pivotal role in prefrontal dopamine signaling, displaying associations with aggressive behavior, and potentially influencing the effects of tDCS. In a double-blind, sham-controlled study, we investigated the influence of rs4680 on tDCS effects on aggression. While undergoing functional magnetic resonance imaging, 89 healthy male participants performed the Taylor aggression paradigm before and immediately after tDCS. Actively stimulated participants (n = 45) received anodal tDCS (1.5 mA) for 20 min targeting the right DLPFC. Carriers of the val-allele (val+; n = 46; active tDCS n = 23) were compared to met-allele homozygotes (val-; n = 43; active tDCS n = 22). Analysis revealed decreased aggressive behavior in the val- group following active tDCS (p < 0.001). The val+ group showed increased aggression during the second session (p < 0.001) with an even higher increase following active as compared to sham tDCS (p < 0.001). No effects of stimulation or rs4680 on brain activation were found. Our study provides evidence for opposite tDCS effects on aggressive behavior in val-carriers and val-noncarriers. By shedding light on genetic factors predicting tDCS responsivity, the study will help to pave the way toward individualized-and thus more effective-tDCS treatment options.

Empathy in schizophrenia: neural alterations during emotion recognition and affective sharing.

Introduction: Deficits in emotion recognition and processing are characteristic for patients with schizophrenia [SCZ]. Methods: We targeted both emotion recognition and affective sharing, one in static and one in dynamic facial stimuli, during functional magnetic resonance imaging [fMRI] in 22 SCZ patients and 22 matched healthy controls [HC]. Current symptomatology and cognitive deficits were assessed as potential influencing factors. Results: Behaviorally, patients only showed a prolonged response time in age-discrimination trials. For emotion-processing trials, patients showed a difference in neural response, without an observable behavioral correlate. During emotion and age recognition in static stimuli, a reduced activation of the bilateral anterior cingulate cortex [ACC] and the right anterior insula [AI] emerged. In the affective sharing task, patients showed a reduced activation in the left and right caudate nucleus, right AI and inferior frontal gyrus [IFG], right cerebellum, and left thalamus, key areas of empathy. Discussion: We conclude that patients have deficits in complex visual information processing regardless of emotional content on a behavioral level and that these deficits coincide with aberrant neural activation patterns in emotion processing networks. The right AI as an integrator of these networks plays a key role in these aberrant neural activation patterns and, thus, is a promising candidate area for neurofeedback approaches.

Effective connectivity of the human cerebellum during visual attention.

Insights from both lesion and neuroimaging studies increasingly substantiate the view that the human cerebellum not only serves motor control but also supports various cognitive processes. Higher cognitive functions like working memory or executive control have been associated with the phylogenetically younger parts of the cerebellum, crus I and crus II. Functional connectivity studies corroborate this notion as activation of the cerebellum correlates with activity in numerous areas of the cerebral cortex. Moreover, these cerebrocerebellar loops were shown to be topographically organized. We used an attention-to-motion paradigm to elaborate on the effective connectivity of cerebellar crus I during visual attention. Psychophysiological interaction analyses demonstrated enhanced connectivity of the cerebellum--during attention--with dorsal visual stream regions including posterior parietal cortex (PPC) and left secondary visual cortex (V5). Dynamic causal modeling revealed a modulation of the connections from V5 to PPC and from crus I to V5 by attention. Remarkably, the influence which V5 exerted on PPC was reduced during attention, resulting in a suppression of the sensitivity of PPC to bottom-up information. Moreover, the sensitivity of V5 populations to inputs from crus I was increased under attention. This might underscore the presumed role of the cerebellum as a state estimator that provides hierarchically lower regions (V5) with top-down predictions, which in turn might be based on endogenous inputs from PPC to the cerebellum. These results are in line with formulations of attention in predictive coding, where attention increases the precision or sensitivity of hierarchically lower neuronal populations that may encode prediction error.

Cognitive Stress Regulation in Schizophrenia Patients and Healthy Individuals: Brain and Behavior.

Stress is an important factor in the development, triggering, and maintenance of psychotic symptoms. Still, little is known about the neural correlates of cognitively regulating stressful events in schizophrenia. The current study aimed at investigating the cognitive down-regulation of negative, stressful reactions during a neuroimaging psychosocial stress paradigm (non-regulated stress versus cognitively regulated stress). In a randomized, repeated-measures within-subject design, we assessed subjective reactions and neural activation in schizophrenia patients (SZP) and matched healthy controls in a neuroimaging psychosocial stress paradigm. In general, SZP exhibited an increased anticipation of stress compared to controls (p = 0.020). During non-regulated stress, SZP showed increased negative affect (p = 0.033) and stronger activation of the left parietal operculum/posterior insula (p < 0.001) and right inferior frontal gyrus/anterior insula (p = 0.005) than controls. Contrarily, stress regulation compared to non-regulated stress led to increased subjective reactions in controls (p = 0.003) but less deactivation in SZP in the ventral anterior cingulate cortex (p = 0.027). Our data demonstrate stronger reactions to and anticipation of stress in patients and difficulties with cognitive stress regulation in both groups. Considering the strong association between mental health and stress, the investigation of cognitive regulation in individuals vulnerable to stress, including SZP, has crucial implications for improving stress intervention trainings.

Multimodal human communication--targeting facial expressions, speech content and prosody.

Human communication is based on a dynamic information exchange of the communication channels facial expressions, prosody, and speech content. This fMRI study elucidated the impact of multimodal emotion processing and the specific contribution of each channel on behavioral empathy and its prerequisites. Ninety-six video clips displaying actors who told self-related stories were presented to 27 healthy participants. In two conditions, all channels uniformly transported only emotional or neutral information. Three conditions selectively presented two emotional channels and one neutral channel. Subjects indicated the actors' emotional valence and their own while fMRI was recorded. Activation patterns of tri-channel emotional communication reflected multimodal processing and facilitative effects for empathy. Accordingly, subjects' behavioral empathy rates significantly deteriorated once one source was neutral. However, emotionality expressed via two of three channels yielded activation in a network associated with theory-of-mind-processes. This suggested participants' effort to infer mental states of their counterparts and was accompanied by a decline of behavioral empathy, driven by the participants' emotional responses. Channel-specific emotional contributions were present in modality-specific areas. The identification of different network-nodes associated with human interactions constitutes a prerequisite for understanding dynamics that underlie multimodal integration and explain the observed decline in empathy rates. This task might also shed light on behavioral deficits and neural changes that accompany psychiatric diseases.

The differential contribution of facial expressions, prosody, and speech content to empathy.

BACKGROUND: Facial expressions, prosody, and speech content constitute channels by which information is exchanged. Little is known about the simultaneous and differential contribution of these channels to empathy when they provide emotionality or neutrality. Especially neutralised speech content has gained little attention with regards to influencing the perception of other emotional cues. METHODS: Participants were presented with video clips of actors telling short-stories. One condition conveyed emotionality in all channels while the other conditions either provided neutral speech content, facial expression, or prosody, respectively. Participants judged the emotion and intensity presented, as well as their own emotional state and intensity. Skin conductance served as a physiological measure of emotional reactivity. RESULTS: Neutralising channels significantly reduced empathic responses. Electrodermal recordings confirmed these findings. The differential effect of the communication channels on empathy prerequisites was that target emotion recognition of the other decreased mostly when the face was neutral, whereas decreased emotional responses attributed to the target emotion were especially present in neutral speech. CONCLUSION: Multichannel integration supports conscious and autonomous measures of empathy and emotional reactivity. Emotional facial expressions influence emotion recognition, whereas speech content is important for responding with an adequate own emotional state, possibly reflecting contextual emotion-appraisal.

Trimodal processing of complex stimuli in inferior parietal cortex is modality-independent.

In humans, multisensory mechanisms facilitate object processing through integration of sensory signals that match in their temporal and spatial occurrence as well as their meaning. The generalizability of such integration processes across different sensory modalities is, however, to date not well understood. As such, it remains unknown whether there are cerebral areas that process object-related signals independently of the specific senses from which they arise, and whether these areas show different response profiles depending on the number of sensory channels that carry information. To address these questions, we presented participants with dynamic stimuli that simultaneously emitted object-related sensory information via one, two, or three channels (sight, sound, smell) in the MR scanner. By comparing neural activation patterns between various integration processes differing in type and number of stimulated senses, we showed that the left inferior frontal gyrus and areas within the left inferior parietal cortex were engaged independently of the number and type of sensory input streams. Activation in these areas was enhanced during bimodal stimulation, compared to the sum of unimodal activations, and increased even further during trimodal stimulation. Taken together, our findings demonstrate that activation of the inferior parietal cortex during processing and integration of meaningful multisensory stimuli is both modality-independent and modulated by the number of available sensory modalities. This suggests that the processing demand placed on the parietal cortex increases with the number of sensory input streams carrying meaningful information, likely due to the increasing complexity of such stimuli.

Effect of odor pleasantness on heat-induced pain: An fMRI study.

Odor modulates the experience of pain, but the neural basis of how the two sensory modalities, olfaction and pain, are linked in the central nervous system is far from clear. In this study, we investigated the mechanisms by which the brain modulates the pain experience under concurrent odorant stimulation. We conducted an fMRI study using a 2 × 3 factorial design, in which one of two temperatures (warm, hot) and one of three types of odors (pleasant, unpleasant, no odor) were presented simultaneously. "Hot" temperatures were individually determined as those perceived as painful (mean temperature = 46.9 °C). The non-painful "warm" temperature was set to 40 °C. Participants rated hot compared to warm stimuli as more intense and unpleasant, especially in the presence of an unpleasant odor. Parametric modeling on the intensity ratings activated the pain network, covering brain regions activated by the hot stimuli. The presence of an odor, irrespective of its valence, activated the amygdalae. In addition, the amygdalae showed stimulus-dependent functional couplings with the right supramarginal gyrus and with the left superior frontal gyrus. The coupling between the right amygdala and the left superior frontal gyrus was related to the intensity and unpleasantness ratings of the pain experience. Our results suggest that these functional connections may reflect the integrating process of the two sensory modalities, enabling olfactory influence on the pain experience.

People expressing olfactory and visual cues of disease are less liked.

For humans, like other social animals, behaviour acts as a first line of defence against pathogens. A key component is the ability to detect subtle perceptual cues of sick conspecifics. The present study assessed the effects of endotoxin-induced olfactory and visual sickness cues on liking, as well as potential involved mechanisms. Seventy-seven participants were exposed to sick and healthy facial pictures and body odours from the same individual in a 2 × 2 factorial design while disgust-related facial electromyography (EMG) was recorded. Following exposure, participants rated their liking of the person presented. In another session, participants also answered questionnaires on perceived vulnerability to disease, disgust sensitivity and health anxiety. Lower ratings of liking were linked to both facial and body odour disease cues as main effects. Disgust, as measured by EMG, did not seem to be the mediating mechanism, but participants who perceived themselves as more prone to disgust, and as more vulnerable to disease, liked presented persons less irrespectively of their health status. Concluding, olfactory and visual sickness cues that appear already a few hours after the experimental induction of systemic inflammation have implications for human sociality and may as such be a part of a behavioural defence against disease. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

Olfactory Communication of Sickness Cues in Respiratory Infection.

Animals detect sick conspecifics by way of body odor that enables the receiver to avoid potential infectious transmission. Human observational studies also indicate that different types of disease are associated with more or less aversive smells. In addition, body odors from otherwise healthy human individuals smell more aversive as a function of experimentally induced systemic inflammation. To investigate if naturally occurring immune activation also gives rise to perceivable olfactory changes, we collected body odor samples during two nights from individuals with a respiratory infection as well as when they were healthy. We hypothesized that independent raters would rate the body odor originating from sick individuals as smelling more aversive than when the same individuals were healthy. Even though body odor samples from sick individuals nominally smelled more intense, more disgusting, and less pleasant and healthy than the body odor from the same individuals when healthy, these effects were not statistically significant. Moreover, raters filled out three questionnaires, Perceived Vulnerability to Disease, Disgust Scale, and Health Anxiety, to assess potential associations between sickness-related personality traits and body odor perception. No such association was found. Since experimentally induced inflammation have made body odors more aversive in previous studies, we discuss whether this difference between studies is due to the level of sickness or to the type of trigger of the sickness response.

Neurobiological Divergence of the Positive and Negative Schizophrenia Subtypes Identified on a New Factor Structure of Psychopathology Using Non-negative Factorization: An International Machine Learning Study.

BACKGROUND: Disentangling psychopathological heterogeneity in schizophrenia is challenging, and previous results remain inconclusive. We employed advanced machine learning to identify a stable and generalizable factorization of the Positive and Negative Syndrome Scale and used it to identify psychopathological subtypes as well as their neurobiological differentiations. METHODS: Positive and Negative Syndrome Scale data from the Pharmacotherapy Monitoring and Outcome Survey cohort (1545 patients; 586 followed up after 1.35 ± 0.70 years) were used for learning the factor structure by an orthonormal projective non-negative factorization. An international sample, pooled from 9 medical centers across Europe, the United States, and Asia (490 patients), was used for validation. Patients were clustered into psychopathological subtypes based on the identified factor structure, and the neurobiological divergence between the subtypes was assessed by classification analysis on functional magnetic resonance imaging connectivity patterns. RESULTS: A 4-factor structure representing negative, positive, affective, and cognitive symptoms was identified as the most stable and generalizable representation of psychopathology. It showed higher internal consistency than the original Positive and Negative Syndrome Scale subscales and previously proposed factor models. Based on this representation, the positive-negative dichotomy was confirmed as the (only) robust psychopathological subtypes, and these subtypes were longitudinally stable in about 80% of the repeatedly assessed patients. Finally, the individual subtype could be predicted with good accuracy from functional connectivity profiles of the ventromedial frontal cortex, temporoparietal junction, and precuneus. CONCLUSIONS: Machine learning applied to multisite data with cross-validation yielded a factorization generalizable across populations and medical systems. Together with subtyping and the demonstrated ability to predict subtype membership from neuroimaging data, this work further disentangles the heterogeneity in schizophrenia.