Abstract
Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by ...currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.
Cognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a "bottom-up" cognitive remediation intervention with efficacy for neurocognitive ...outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R
= 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R
= 0.40) and negative (SANS, R
= 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R
< 0.06). The results indicate that the capacity to support gamma oscillations, as well as the plasticity of the underlying ASSR circuitry after acute exposure to 1 h of TCT, reflect neural mechanisms underlying the efficacy of TCT, and may be used to predict individualized treatment outcomes. These findings suggest that gamma oscillatory biomarkers applied within the context of experimental medicine designs can be used to personalize individual treatment options for pro-cognitive interventions in patients with schizophrenia.
Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in ...schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.
Aim
Gamma‐band auditory steady‐state response (ASSR) is a neurophysiologic index that is increasingly used as a translational biomarker in the development of treatments of neuropsychiatric disorders. ...While gamma‐band ASSR is generated by distributed networks of highly interactive temporal and frontal cortical sources, the majority of human gamma‐band ASSR studies using electroencephalography (EEG) highlight activity from only a single frontocentral scalp site, Fz, where responses tend to be largest and reductions in schizophrenia patients are most evident. However, no previous study has characterized the relative source contributions to Fz, which is a necessary step to improve the concordance of preclinical and clinical EEG studies.
Methods
A novel method to back‐project the contributions of independent cortical source components was applied to assess the independent sources and their proportional contributions to Fz as well as source‐resolved responses in 432 schizophrenia patients and 294 healthy subjects.
Results
Independent contributions of gamma‐band ASSR to Fz were detected from orbitofrontal, bilateral superior/middle/inferior temporal, bilateral middle frontal, and posterior cingulate gyri in both groups. In contrast to expectations, the groups showed comparable source contribution weight to gamma‐band ASSR at Fz. While gamma‐band ASSR reductions at Fz were present in schizophrenia patients consistent with previous studies, no group differences in individual source‐level responses to Fz were detected.
Conclusion
Small differences in multiple independent sources summate to produce scalp‐level differences at Fz. The identification of independent source contributions to a single scalp sensor represents a promising methodology for measuring dissociable and homologous biomarker targets in future translational studies.
The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive ...cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.
Gamma-band (40-Hz) activity is critical for cortico-cortical transmission and the integration of information across neural networks during sensory and cognitive processing. Patients with ...schizophrenia show selective reductions in the capacity to support synchronized gamma-band oscillations in response to auditory stimulation presented 40-Hz. Despite widespread application of this 40-Hz auditory steady-state response (ASSR) as a translational electroencephalographic biomarker for therapeutic development for neuropsychiatric disorders, the spatiotemporal dynamics underlying the ASSR have not been fully characterized. In this study, a novel Granger causality analysis was applied to assess the propagation of gamma oscillations in response to 40-Hz steady-state stimulation across cortical sources in schizophrenia patients (n = 426) and healthy comparison subjects (n = 293). Both groups showed multiple ASSR source interactions that were broadly distributed across brain regions. Schizophrenia patients showed distinct, hierarchically sequenced connectivity abnormalities. During the response onset interval, patients exhibited abnormal increased connectivity from the inferior frontal gyrus to the superior temporal gyrus, followed by decreased connectivity from the superior temporal to the middle cingulate gyrus. In the later portion of the ASSR response (300–500 ms), patients showed significantly increased connectivity from the superior temporal to the middle frontal gyrus followed by decreased connectivity from the left superior frontal gyrus to the right superior and middle frontal gyri. These findings highlight both the orchestration of distributed multiple sources in response to simple gamma-frequency stimulation in healthy subjects as well as the patterns of deficits in the generation and maintenance of gamma-band oscillations across the temporo-frontal sources in schizophrenia patients.
•Schizophrenia patients show 40-Hz auditory steady-state response (ASSR) reductions.•The spatiotemporal dynamics underlying the ASSR have not yet been characterized.•In this study, we assessed the propagation of gamma oscillations across cortical sources.•40-Hz ASSR deficits reflect a connectivity abnormality across temporofrontal regions.•These findings will strengthen the utility of 40-Hz ASSR as a translational marker.
Schizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust ...translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs. non-shared variance in cognitive, clinical, and psychosocial functioning.
Multiple regression analyses with MMN, gamma-band ASSR, and clinical measures were performed in large cohorts of schizophrenia outpatients (N = 428) and healthy comparison subjects (N = 283).
Reduced MMN (d = 0.67), gamma-band ASSR (d = −0.40), and lower cognitive function were confirmed in schizophrenia patients. Regression analyses revealed that reduced MMN amplitude showed unique associations with lower verbal learning and negative symptoms, reduced gamma-band ASSR showed a unique association with working memory deficits, and both reduced MMN amplitude and reduced gamma-band ASSR showed an association with daily functioning impairment in schizophrenia patients.
MMN and ASSR measures are non-redundant and complementary measures of early auditory information processing that are associated with important domains of functioning. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR to improve our understanding of the pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions.
Gamma band activity has been associated with many sensory and cognitive functions, and is important for cortico-cortical transmission and the integration of information across neural networks. The ...aims of the present study were to determine if schizophrenia patients have deficits in the generation and maintenance of coherent, synchronized oscillations in response to steady-state stimulation, and to examine the clinical and cognitive correlates of the electroencephalography (EEG) oscillatory dynamics.
Schizophrenia patients (
n = 100) and nonpsychiatric subjects (
n = 80) underwent auditory steady-state event-related potential testing. Click trains varying in rate of stimulation (20, 30, and 40 Hz) were presented; EEG-evoked power and intertrial phase synchronization were obtained in response to each stimulation frequency. Subjects also underwent clinical and neurocognitive assessments.
Patients had reductions in both evoked power and phase synchronization in response to 30- and 40-Hz stimulation but normal responsivity to 20-Hz stimulation. Maximal deficits were detected in response to 40-Hz stimulation. A modest association of reduced working memory performance and 40-Hz intertrial phase synchronization was present in schizophrenia patients (
r = .32,
p <.01).
Schizophrenia patients have frequency-specific deficits in the generation and maintenance of coherent gamma-range oscillations, reflecting a fundamental degradation of basic integrated neural network activity.
Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes ...exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.
Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.
Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.
The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related ...potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients.
410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA.
SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior–posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli.
MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.
► Large cohort of research participants (410 SZ patients, 247 NCS) ► MMN/P3a networks distributed across temporal, frontal, and parietal regions ► MMN deficits associated with reduced activation of discrete medial frontal regions ► P3a deficits associated with reductions in temporal, frontal, and parietal regions ► Results consistent with hierarchical “cascade” models of SZ deficits
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