David Leitman

Objective: Humans are social creatures, with desires to connect or belong, producing loneliness when isolated. Individuals with schizophrenia are often more isolated than healthy adults and demonstrate profound social communication impairments such as vocal affect perception (prosody). Loneliness, levels of desire for social connectedness (need to belong, NTB), and their relationship to perception of social communications have not been investigated in schizophrenia. Method: In a sample of 69 individuals (36 SZ), we measured endorsements of loneliness and NTB, and evaluated their putative relationships to clinical symptoms and social communication abilities, as indexed by emotional prosody and pitch perception. Results: Loneliness endorsement was highly variable but particularly so in patients, whilst patients endorsed NTB at levels equivalent to healthy controls. In schizophrenia, pitch and prosody acuity were reduced, and prosody perception correlated with NTB. Loneliness, but not ...

Background: Perceiving social intent throughvocal intonation is impaired in schizophrenia; thisdysprosodia partly arisingfrom impaired pitch perception.Individuals with amusia (tone-deafness) are insensitive to pitch change andalso demonstrate prosody deficits. Sensitivity to rhythm is reduced in amusia when tonal sequences contain pitch changes (polytonic), but is normal for monotonic sequences, suggestingperceptual impairment originates at a secondary processing stage where pitch- and time- relatedcues are yoked.Here, we sought to ascertain: 1) whether schizophreniapatients demonstrate rhythmic deficits, 2) whether suchdeficits are restricted to polytonic sequences, and 3) how pitch and rhythm perception relate to prosodic processing.Methods: Seventy-sixparticipants (33 schizophrenia) completed tasks assessing pitch and prosody perception, as well as monotonic and polytonic rhythmic perception. Results: Increasing tone-deafness correlated with pitch-dependent rhythm detection impa...

Patients with schizophrenia display abnormalities in pitch discrimination of non-verbal tones as revealed by the Tone-Matching Task (TMT). It may lead to deficits in higher-order cognitive functions and clinical symptoms. We conducted a systematic review and meta-analysis pooling data about TMT score differences between patients with schizophrenia and healthy controls, to evaluate the deficit's effect size, and to develop reliable knowledge about pitch processing impairment and its pejorative impact. Relevant publications were identified by a systematic search of PubMed and EMBASE databases. Then, we excluded non-relevant studies for the meta-analysis. Effect size for percent of correct responses to the TMT was expressed as standardized mean difference (SMD). Eighteen of 167 identified studies met eligibility criteria for review, of which 10 were included in the meta-analysis. Our meta-analysis showed that the effect size for the percent of correct response to the TMT between patients (N=371) and controls (N=342) was large: SMD=1.17 [95% CI: 0.926-1.418] (z-value=9.338 and p-value<0.001). Meta-analysis showed moderate heterogeneity between studies (Q(9)=17.22, p=0.04, I2=47.74%). The relationship between tone-matching impairment and clinical symptoms of schizophrenia remains heterogeneous across studies. Some authors observed significant correlations between tone-matching performance and a number of higher-order cognitive abilities. This review and meta-analysis highlights a large significant disturbance in tone-matching ability in patients as compared with controls. The study of basic auditory processing opens promising perspectives for pathophysiological modelling of the disorder and therapeutic issues.

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal ("prosodic") features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and r...

Both elevated cardiovascular mortality and low cardio-vagal (parasympathetic) heart rate variability (HRV)--a risk factor for postmyocardial infarction--are reported in schizophrenia (SZ). Since a number of medications have strong effects of cardiac conductivity, we thought it important to examine if typical neuroleptic medications might also affect HRV. We examined cardiac vagal activity during both neuroleptic treatment and a drug-free condition in seven SZ patients who were participating in a pilot double-blind, crossover study of placebo and haloperidol treatment. Twenty-four-hour Holter electrocardiograms were analyzed for high frequency HRV, quantitated as the percent of successive normal interbeat intervals greater than 50 milliseconds (PNN50), which is a good index of parasympathetic cardiac modulation. The patients showed unchanged PNN50 (8.4+/-9.5 versus 8.3+/-10.5; t=.22, df=6, P=.5) between the haloperidol treatment and drug-free conditions. Despite the elapsed time, cha...

It has long been considered that psychosocial stress plays a role in the expression of symptoms in schizophrenia (SZ), as it interacts with latent neural vulnerability that stems from genetic liability and early environmental insult. Advances in the understanding of the neurobiology of the stress cascade in both animal and human studies lead to a plausible model by which this interaction may occur: through neurotoxic effects on the hippocampus that may involve synaptic remodeling. Of late, the neurodevelopmental model of SZ etiology has been favored. But an elaboration of this schema that credits the impact of postnatal events and considers a role for neurodegenerative changes may be more plausible, given the evidence for gene-environment interaction in SZ expression and progressive structural changes observed with magnetic resonance imaging. Furthermore, new insights into nongliotic neurotoxic effects such as apoptosis, failure of neurogenesis, and changes in circuitry lead to an e...

Smell identification deficits are consistently found in schizophrenia (SZ), but little is known about the nature and characterization of this deficit or its relationship to the phenomenology of the illness. This study aims to further delineate smell identification errors in SZ by examining the relationship of patient demographic differences with smell-identification performance. Our results showed that a patient's gender and education were related to odor-identification scores, with better performance seen in female patients and in those with greater educational attainment. However, there was no effect related to age, ethnicity, or socioeconomic status on odor identification. A smell identification deficit was also unrelated to clinical characteristics of the patients, including age at first hospitalization, number of psychiatric hospitalizations, and duration of illness. Odor identification also did not differ by SZ subtype, nor between SZ and schizoaffective disorder patients....

Intact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia. Auditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory performance. Patients showed large effect-size deficits across auditory measures. Sarcasm deficits correlated significantly with general functioning and impaired pitch processing both across groups and within the patient group alone. Patients also showed reduced sensitivity to alterations in mean pitch and variability. For patients, sarcasm discrimination correlated exclusively with the level of rsFC within primary auditory regions whereas for controls, correlations were observed exclusively within core-mentalizing regions (the right posterior superior temporal gyrus, anterior superior temporal sulcus and insula, and left posterior medial temporal gyrus). These findings confirm the contribution of auditory deficits to theory of mind (ToM) impairments in schizophrenia, and demonstrate that FC within auditory, but not core-mentalizing, regions is rate limiting with respect to sarcasm detection in schizophrenia.

This review explores the neurobiology of stress and its possible role in the etiology of schizophrenia. Major life events may play a role in onset and relapse in schizophrenia. Other data suggest that early stress exposure increases schizophrenia risk, especially in individuals with latent vulnerability. Animal research has led to an elucidation of the mechanisms by which stress and cortisol are toxic to the hippocampus and impair cognition. Associations among these factors have been found in a variety of human conditions, including psychiatric illness and normal aging. These mechanisms are plausible in schizophrenia, which is characterized by a degree of cortisol dysregulation, hippocampal abnormality, and cognitive impairment. Characterization of the role of the stress cascade in schizophrenia has implications for novel pharmacologic and other treatment, especially for cognitive symptoms, which are debilitating and largely refractory to treatment.

Modulation of speech conveys information that is decoded within audio-sensory structures. For example, the termination of an utterance with a rise in pitch distinguishes statements and questions. This study evaluated the sensitivity of early auditory structures to such linguistic prosodic distinctions using mismatch negativity (MMN). MMN is a preattentive auditory event-related potential (ERP) sensitive to stimulus deviance. High-density ERP to pitch contour stimuli were collected in a passive listening oddball paradigm from 11 healthy subjects. Voltage analysis revealed significant MMN responses to declarative and interrogative oddball stimuli. Further, MMN was significantly larger to interrogative, than declarative, deviants, indicating non-symmetric brain processing. These MMNs demonstrate that pitch contour abstractions reflecting interrogative/ declarative distinctions can be represented in preattentive auditory sensory memory.

Deficits in affect recognition are prominent features of schizophrenia. Within the auditory domain, patients show difficulty in interpreting vocal emotional cues based on intonation (prosody). The relationship of these symptoms to deficits in basic sensory processing has not been previously evaluated. Forty-three patients and 34 healthy comparison subjects were tested on two affective prosody measures: voice emotion identification and voice emotion discrimination. Basic auditory sensory processing was measured using a tone-matching paradigm and the Distorted Tunes Test (DTT). A subset of subjects was also tested on facial affect identification and discrimination tasks. Patients showed significantly impaired performance on all emotion processing tasks. Within the patient group, a principal components analysis demonstrated significant intercorrelations between basic pitch perception and affective prosodic performance. In contrast, facial affect recognition deficits represented a distinct second component. Prosodic affect measures correlated significantly with severity of negative symptoms and impaired global outcome. These results demonstrate significant relationships between basic auditory processing deficits and impaired receptive prosody in schizophrenia. The separate loading of auditory and visual affective recognition measures suggests that within-modality factors may be more significant than cross-modality factors in the etiology of affect recognition deficits in schizophrenia.

Schizophrenia patients have vocal affect (prosody) deficits that are treatment resistant and associated with negative symptoms and poor outcome. The neural correlates of this dysfunction are unclear. Prior study has suggested that schizophrenia vocal affect perception deficits stem from an inability to use acoustic cues, notably pitch, in decoding emotion. Functional magnetic resonance imaging was performed in 24 schizophrenia patients and 28 healthy control subjects, during the performance of a four-choice (happiness, fear, anger, neutral) vocal affect identification task in which items for each emotion varied parametrically in affective salient acoustic cue levels. We observed that parametric increases in cue levels in schizophrenia failed to produce the same identification rate increases as in control subjects. These deficits correlated with diminished reciprocal activation changes in superior temporal and inferior frontal gyri and reduced temporo-frontal connectivity. Task activation also correlated with independent measures of pitch perception and negative symptom severity. These findings illustrate the interplay between sensory and higher-order cognitive dysfunction in schizophrenia. Sensory contributions to vocal affect deficits also suggest that this neurobehavioral marker could be targeted by pharmacological or behavioral remediation of acoustic feature discrimination.

Schizophrenia is characterized by widespread cognitive deficits that reflect distributed dysfunction across multiple cortical regions. Here the authors examined the relationship between lower- and higher-level dysfunction within the auditory domain using the event-related brain potentials mismatch negativity (MMN) and P300. Event-related brain potentials were obtained from 50 schizophrenia patients and 21 healthy subjects in two conditions: a standard condition employing fixed differences between standard tones and pitch deviants and a novel individualized condition employing tones matched to each individual's tone-discrimination threshold. The relationship among measures was assessed by multiple regression analysis and structural equation modeling. In the standard fixed-deviance condition, schizophrenia patients showed deficits of large effect size in generation of MMN (d>1.26) and P300 (d=1.08) relative to comparison subjects. Assessment of deviance-detection thresholds showed that patients required significantly elevated tone-matching thresholds relative to comparison subjects (d=0.97). When tone differences were individually adjusted to equate tone-matching performance across groups, the groups no longer differed significantly in MMN amplitude during deviant pitch tones, and the degree of deficit in P300 generation was significantly reduced. In both multiple regression analysis and structural equation modeling, MMN and diagnostic group were significant independent predictors of reduced P300 amplitude. MMN generation was well explained (>90% variance) by dipoles seeded within the bilateral auditory cortex. These findings confirm and extend previous reports of impaired basic sensory processing in schizophrenia and demonstrate significant contributions of early sensory processing dysfunction to higher-order cognitive impairments. Overall, the findings support distributed, hierarchical models of cognitive impairment in schizophrenia, consistent with glutamatergic and other widespread neurochemical models of the disorder.

Schizophrenia is associated with deficits in the ability to perceive emotion based on tone of voice. The basis for this deficit remains unclear, however, and relevant assessment batteries remain limited. The authors evaluated performance in schizophrenia on a novel voice emotion recognition battery with well-characterized physical features, relative to impairments in more general emotional and cognitive functioning. The authors studied a primary sample of 92 patients and 73 comparison subjects. Stimuli were characterized according to both intended emotion and acoustic features (e.g., pitch, intensity) that contributed to the emotional percept. Parallel measures of visual emotion recognition, pitch perception, general cognition, and overall outcome were obtained. More limited measures were obtained in an independent replication sample of 36 patients, 31 age-matched comparison subjects, and 188 general comparison subjects. Patients showed statistically significant large-effect-size deficits in voice emotion recognition (d=1.1) and were preferentially impaired in recognition of emotion based on pitch features but not intensity features. Emotion recognition deficits were significantly correlated with pitch perception impairments both across (r=0.56) and within (r=0.47) groups. Path analysis showed both sensory-specific and general cognitive contributions to auditory emotion recognition deficits in schizophrenia. Similar patterns of results were observed in the replication sample. The results demonstrate that patients with schizophrenia show a significant deficit in the ability to recognize emotion based on tone of voice and that this deficit is related to impairment in detecting the underlying acoustic features, such as change in pitch, required for auditory emotion recognition. This study provides tools for, and highlights the need for, greater attention to physical features of stimuli used in studying social cognition in neuropsychiatric disorders.