Temporal and Spectral Properties of the Auditory Mismatch Negativity and P3a Responses in Schizophrenia.

The mismatch negativity (MMN) event-related potential (ERP) indexes relatively automatic detection of changes in sensory stimuli and is typically attenuated in individuals with schizophrenia. However, contributions of different frequencies of electroencephalographic (EEG) activity to the MMN and the later P3a attentional orienting response in schizophrenia are poorly understood and were the focus of the present study. Participants with a schizophrenia-spectrum disorder (n = 85) and non-psychiatric control participants (n = 74) completed a passive auditory oddball task containing 10% 50 ms "deviant" tones and 90% 100 ms "standard" tones. EEG data were analyzed using spatial principal component analysis (PCA) applied to wavelet-based time-frequency analysis and MMN and P3a ERPs. The schizophrenia group compared to the control group had smaller MMN amplitudes and lower deviant-minus-standard theta but not alpha event-related spectral perturbation (ERSP) after accounting for participant age and sex. Larger MMN and P3a amplitudes but not latencies were correlated with greater theta and alpha time-frequency activity. Multiple linear regression analyses revealed that control participants showed robust relationships between larger MMN amplitudes and greater deviant-minus-standard theta inter-trial coherence (ITC) and between larger P3a amplitudes and greater deviant-minus-standard theta ERSP, whereas these dynamic neural processes were less tightly coupled in participants with a schizophrenia-spectrum disorder. Study results help clarify frequency-based contributions of time-domain (ie, ERP) responses and indicate a potential disturbance in the neural dynamics of detecting change in sensory stimuli in schizophrenia. Overall, findings add to the growing body of evidence that psychotic illness is associated with widespread neural dysfunction in the theta frequency band.

Abnormal beta and gamma frequency neural oscillations mediate auditory sensory gating deficit in schizophrenia.

BACKGROUND: Sensory gating is a process in which the brain's response to irrelevant and repetitive stimuli is inhibited. The sensory gating deficit in schizophrenia (SZ) is typically measured by the ratio or difference score of the P50 event-related potential (ERP) amplitudes in response to a paired click paradigm. While the P50 gating effect has usually been measured in relation to the peak amplitude of the S1 and S2 P50 ERPs, there is increasing evidence that inhibitory processes may be reflected by evoked or induced oscillatory activity during the inter-click interval in the beta (20-30 Hz) and gamma (30-50 Hz) frequency bands. We therefore examined the relationship between frequency specific activity in the inter-click interval with gating effects in the time and frequency domains. METHOD: Paired-auditory stimuli were presented to 131 participants with schizophrenia and 196 healthy controls (HC). P50 ERP amplitudes to S1 and S2as well as averaged- and single-trial beta (20-30 Hz) and gamma (30-50 Hz) frequency power during the inter-click interval were measured from the CZ electrode site. RESULTS: In the time domain, P50 gating deficits were apparent in both ratio and difference scores. This effect was mainly due to smaller S1 amplitudes in the patient group. SZ patients exhibited less evoked beta and gamma power, particularly at the 0-100 ms time point, in response to S1. Early (0-100 ms) evoked beta and gamma responses were critical in determining the S1 amplitude and extent of P50 gating across the delay interval for both HC and SZ. CONCLUSION: Our findings support a disruption in initial sensory registration in those with SZ, and do not support an active mechanism throughout the delay interval. The degree of response to S1 and early beta and gamma frequency oscillations in the delay interval provides information about the mechanisms supporting auditory sensory gating, and may provide a framework for studying the mechanisms that support sensory inhibition.

Impaired Effective Connectivity During a Cerebellar-Mediated Sensorimotor Synchronization Task in Schizophrenia.

Prominent conceptual models characterize schizophrenia as a dysconnectivity syndrome, with recent research focusing on the contributions of the cerebellum in this framework. The present study examined the role of the cerebellum and its effective connectivity to the cerebrum during sensorimotor synchronization in schizophrenia. Specifically, the role of the cerebellum in temporally coordinating cerebral motor activity was examined through path analysis. Thirty-one individuals diagnosed with schizophrenia and 40 healthy controls completed a finger-tapping fMRI task including tone-paced synchronization and self-paced continuation tapping at a 500 ms intertap interval (ITI). Behavioral data revealed shorter and more variable ITIs during self-paced continuation, greater clock (vs motor) variance, and greater force of tapping in the schizophrenia group. In a whole-brain analysis, groups showed robust activation of the cerebellum during self-paced continuation but not during tone-paced synchronization. However, effective connectivity analysis revealed decreased connectivity in individuals with schizophrenia between the cerebellum and primary motor cortex but increased connectivity between cerebellum and thalamus during self-paced continuation compared with healthy controls. These findings in schizophrenia indicate diminished temporal coordination of cerebral motor activity by cerebellum during the continuation tapping portion of sensorimotor synchronization. Taken together with the behavioral finding of greater temporal variability in schizophrenia, these effective connectivity results are consistent with structural and temporal models of dysconnectivity in the disorder.

Reduced electroencephalogram responses to standard and target auditory stimuli in bipolar disorder and the impact of psychotic features: Analysis of event-related potentials, spectral power, and inter-trial coherence.

BACKGROUND: Bipolar disorder (BD) is associated with reductions in the P3b event-related potential (ERP) response to target auditory stimuli, which suggests deficits in context updating. Previous studies have typically examined these responses in the temporal domain, which may not capture alterations in specific frequencies of phase-locked or induced electrophysiological activity. Therefore, the present study examined early and late ERPs in temporal and frequency domains in a bipolar sample with and without current psychotic features. METHODS: The electroencephalogram (EEG) was recorded during an auditory oddball task. Seventy-five BD patients and 98 healthy controls (HCs) discriminated between standard and target tones. N1 ERPs to standards and P3b ERPs to targets were analyzed in the temporal domain. Event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were analyzed in the frequency domain. RESULTS: The early N1 response to standard tones was not significantly different between the total HC and BD samples irrespective of psychotic features. However, N1 amplitude was reduced in BD patients with psychotic features (BDP) compared to HCs and BD patients without psychotic features. P3b was reduced in BD patients versus HCs, with the BDP sample having the most reduced amplitude. In the time-frequency analysis, delta and theta ERSP and ITC were reduced across the time window for both standard and target stimuli in BD patients compared to HCs, but did not differ in the psychotic features analysis. CONCLUSIONS: The results provide neural evidence that BD is associated with disrupted sensory, attentional, and cognitive processing of auditory stimuli, which may be worsened with the presence of psychotic features.

Phencyclidine Disrupts the Auditory Steady State Response in Rats.

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

The auditory steady-state response (ASSR): a translational biomarker for schizophrenia.

Electrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non-invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk.

Computer-assisted cognitive remediation for schizophrenia: a randomized single-blind pilot study.

Cognitive impairment is a core symptom in schizophrenia that has a significant impact on psychosocial function, but shows a weak response to pharmacological treatment. Consequently, a variety of cognitive remediation strategies have been evaluated to improve cognitive function in schizophrenia. The efficacy of computer-based cognitive remediation as a stand-alone intervention on general measures of neuropsychological function remains unclear. We tested the effectiveness of biweekly training using computerized cognitive remediation programs on neuropsychological and event-related potential outcome measures. Schizophrenia patients were randomly assigned to cognitive remediation training (N=17), active control (TV-watching; N=17), or treatment-as-usual (N=10) groups for ten weeks and run in parallel. Cognitive and ERP measures revealed no differential improvement over time in the cognitive remediation group. Practice effects might explain change over time on several cognitive measures for all groups, consistent with studies indicating task-specific improvement. Computer-assisted cognitive remediation alone may not be sufficient for robust or generalized effects on cognitive and electrophysiological measures in schizophrenia patients.

The effect of chronic cannabinoids on broadband EEG neural oscillations in humans.

Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10-50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis.

Auditory steady state response in the schizophrenia, first-degree relatives, and schizotypal personality disorder.

The power and phase synchronization of the auditory steady state response (ASSR) at 40 Hz stimulation is usually reduced in schizophrenia (SZ). The sensitivity of the 40 Hz ASSR to schizophrenia spectrum phenotypes, such as schizotypal personality disorder (SPD), or to familial risk has been less well characterized. We compared the ASSR of patients with SZ, persons with schizotypal personality disorder, first degree relatives of patients with SZ, and healthy control participants. ASSRs were obtained to 20, 30, 40 and 50 Hz click trains, and assessed using measures of power (mean trial power or MTP) and phase consistency (phase locking factor or PLF). The MTP to 40 Hz stimulation was reduced in relatives, and there was a trend for MTP reduction in SZ. The 40 Hz ASSR was not reduced in SPD participants. PLF did not differ among groups. These data suggest the 40 Hz ASSR is sensitive to familial risk factors associated with schizophrenia.

Aberrant auditory processing in schizophrenia and in subjects at ultra-high-risk for psychosis.

The N1 and the mismatch negativity (MMN) responses observed in electroencephalographic and magnetoencephalographic (MEG) recordings reflect sensory processing, sensory memory, and adaptation and are usually abnormal in patients with schizophrenia. However, their differential sensitivity to ultra-high-risk (UHR) status is controversial. The current study evaluated the sensitivity of MEG N1m, N1m adaptation, and magnetic counterpart of MMN (MMNm) in 16 UHR subjects, 15 schizophrenia patients, and 18 healthy controls (HCs) during a passive auditory oddball task. N1m adaptation was assessed using the difference in N1m dipole moment between the first and last standard tones in a standard stimulus sequence. N1m adaptation occurred in HCs, whereas neither the UHR nor the schizophrenia groups showed adaptation to the standard tone on repeated presentations. The UHR group had values between those for HCs and schizophrenia patients. Additionally, MMNm dipole moment was reduced in both the UHR and patient groups compared with HCs, whereas the UHR and schizophrenia groups did not differ from each other. These findings indicated that both N1m adaptation and MMNm were altered in UHR subjects and in schizophrenia patients, despite unaffected N1m dipole moment to the first standard tones. Moreover, both UHR and schizophrenia groups failed to show adaptation of the N1m to repeated standard tones. This failure in adaptation was more severe in patients than UHR subjects, suggesting that auditory adaptation may be sensitive to the progression of the illness and be an early biomarker of UHR for psychosis. Deficits in auditory sensory memory, on the other hand, may be similarly impaired in both groups.

A longitudinal twin study of effects of adolescent alcohol abuse on the neurophysiology of attention and orienting.

BACKGROUND: Long-term functional brain effects of adolescent alcohol abuse remain uncertain, partially because of difficulties in distinguishing inherited deficits from neuronal effects of ethanol and by confounds associated with alcohol abuse, especially nicotine exposure. We conducted a longitudinal twin study to determine neurocognitive effects of adolescent alcohol abuse, as measured with the auditory event-related potential (ERP) component P3, a putative marker of genetic vulnerability to alcoholism. METHODS: Twin pairs (N=177; 150 selected for intrapair concordance/discordance for alcohol-related problems at age 18½) were recruited from ongoing studies of twins born 1975-1979 in Finland. Alcohol and tobacco use were assessed with questionnaires at ages 16, 17, 18½, and ~25, and by a structured psychiatric interview concurrent with the ERP testing at mean age 25.8. During ERP recordings, subjects were instructed to detect target tones within a train of frequent "standards" and to ignore occasional "novel" sounds. To distinguish familial factors from ethanol effects, ERP and self-reported alcohol use measures were incorporated into hierarchical multiple regression (HMR) analysis, and intrapair differences in ERP were associated with intra-pair differences in alcohol variables. RESULTS: Novel-sound P3 amplitude correlated negatively with self-reported alcohol use in both between- and within-family analyses. No similar effect was observed for target-tone P3. HMR results suggest that twins' similarity for novel-sound P3 amplitude is modulated by their alcohol use, and this effect of alcohol use is influenced by genetic factors. CONCLUSIONS: Our results, from a large sample of twins selected from a population-based registry for pairwise concordance/discordance for alcohol problems at 18½, demonstrate that adolescent alcohol abuse is associated with subtle neurophysiological changes in attention and orienting. The changes are reflected in decreased novel-sound P3 amplitude and may be modified by genetic factors.

An MEG study of alpha modulation in patients with schizophrenia and in subjects at high risk of developing psychosis.

BACKGROUND: Selective attention involves a dynamic interaction between attentional control systems and brain oscillations. In auditory processing, selective attention toward task-relevant stimuli and the inhibition of irrelevant information can be considered as aspects of top-down attentional control. Oscillatory rhythms in the alpha band have been found to play an important role during top-down processing. Because attention deficits have been noted in patients with schizophrenia, we examined alpha oscillations in schizophrenia and in the prodromal phase of psychosis. METHODS: The present study compared alpha oscillations using measures of both spectral power and inter-trial coherence in 17 subjects at ultra-high-risk, 10 patients with schizophrenia, and 18 matched normal control subjects. Whole-head magnetoencephalography (MEG) was conducted during an auditory oddball task to investigate alpha brain activity related to selective attention to target stimuli and selective inhibition of irrelevant stimuli. RESULTS: Patients with schizophrenia showed diminished alpha event-related desynchronization compared with the control subjects, while the ultra-high-risk subjects had values intermediate between the control subjects and schizophrenia patients. Similarly, alpha inter-trial phase coherence was lower in the schizophrenia patients than the ultra-high-risk subjects, and lower in the ultra-high-risk subjects than the normal control subjects. Furthermore, alpha band activity in the parieto-occipital region was more severely depressed in the schizophrenia patients than the ultra-high-risk subjects. CONCLUSIONS: The altered alpha band activity in the ultra-high-risk group indicates that a deficit in top-down attentional control exists before the onset of psychosis. The alpha event-related desynchronization and inter-trial coherence may reflect a functional decline in the prodromal phase of schizophrenia.

Auditory steady state response in bipolar disorder: relation to clinical state, cognitive performance, medication status, and substance disorders.

OBJECTIVES: Abnormalities in auditory steady state response (ASSR) at gamma range frequencies have been found in bipolar disorder, but the relationship of these neurophysiological disturbances to clinical factors has not been well characterized. We therefore evaluated the ASSR in bipolar disorder and examined its sensitivity to clinical symptoms, cognitive function, and pharmacological treatment. METHODS: A total of 68 patients with bipolar disorder and 77 control participants were evaluated. Click trains presented at 20, 30, 40, and 50 Hz evoked ASSRs. Mean trial power (MTP) and phase locking factor (PLF) measured response magnitude and phase synchronization of the ASSR at each stimulation frequency. Clinical state, pharmacological treatment, and neuropsychological performance were assessed, and their respective relationships with ASSR measures were evaluated. RESULTS: Patients with bipolar disorder showed reduced MTP and PLF compared to control participants. Bipolar disorder patients taking psychotropic medications had decreased PLF relative to patients withdrawn from medications. Control participants performed better on neuropsychological tests than bipolar disorder patients; however, test scores did not correlate with ASSR measures. CONCLUSIONS: Deficits in the generation and maintenance of ASSR are present in bipolar disorder, implicating disturbances in auditory pathways. ASSR may be sensitive to medication status. Other clinical features, including mood state, psychotic features, cognitive performance, smoking, or history of substance use disorder, were unrelated to MTP or PLF.

Increased temporal variability of auditory event-related potentials in schizophrenia and Schizotypal Personality Disorder.

Previous studies suggest that deficits in neural synchronization and temporal integration are characteristic of schizophrenia. These phenomena have been rarely studied in SPD, which shares phenomenological and genetic similarities with schizophrenia. Event-related potentials (ERPs) were obtained using an auditory oddball task from 21 patients with schizophrenia, 19 subjects with SPD and 19 healthy control subjects. Inter-trial coherence (ITC) and event-related spectral perturbation (ERSP) were measured across trials to target tones using time-frequency analysis. ITC measures phase locking or consistency, while ERSP measures changes in power relative to baseline activity. P300 latency and amplitude were also measured from the averaged ERP to target tones. In the time-frequency analysis, subjects with SPD showed intact power but a deficit in the ITC in delta and theta frequencies compared to control subjects. Patients with schizophrenia showed deficits for both ERSP and ITC in the delta and theta frequencies. While patients with schizophrenia showed reduced P300 amplitude and delayed latency for averaged ERPs, subjects with SPD did not differ from either group. Synchronization or timing abnormalities may represent a biomarker for schizophrenia spectrum disorders, and contribute to aberrant perceptual and cognitive integration.

Relationships between auditory event-related potentials and mood state, medication, and comorbid psychiatric illness in patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) exhibit aberrations in auditory event-related potentials (ERPs), although the relationships between these measures and mood state at testing, comorbid psychiatric illness, presence of psychotic features, and medication usage are unclear. The purpose of this study was to investigate the relationships between these factors and auditory ERP measures in BD patients. METHODS: An auditory 'oddball' discrimination task was used to elicit ERPs from 69 patients with type I BD and 52 healthy controls. Patients were placed into subgroups based upon their mood state at testing (euthymic or symptomatic), and ANOVA was used to compare amplitude and peak latency measures from the N100, P200, N200, and P300 ERP components across subgroups. Multiple regression was used to investigate relationships between ERP measures and comorbid psychiatric diagnosis, history of psychotic features, and medication status. RESULTS: Relative to healthy control participants, euthymic and symptomatic BD patients exhibited reduced P300 and P200 amplitude, but ERP measures did not differ among BD patients on the basis of mood status. A history of a comorbid anxiety disorder was associated with reduced N200 peak latency, but prolonged P300 peak latency among BD patients. No other relationships between clinical variables and ERP measures were significant. CONCLUSIONS: The results suggest that disrupted auditory attention may be observed in BD patients regardless of their mood state at testing, medication status, or history of psychosis. These results extend previous findings, and provide further evidence for aberrations in the P300 ERP as an endophenotype for BD.

Event-related potential abnormalities in schizophrenia: a failure to "gate in" salient information?

Sensory gating refers to the central nervous system's ability to filter sensory inputs, and can be measured by comparing the suppression of event-related brain potential (ERP) amplitudes in a paired auditory stimulus procedure. Poor gating scores in schizophrenia may be caused by abnormal responses to the first (S1), the second (S2) or both of the paired stimuli. However, since S1 and S2 responses may index separate psychological phenomenon, corresponding to the ability to "gate in" and "gate out" sensory stimuli respectively, the precise mechanism affected in schizophrenia remains unclear. To examine the extent to which saliency processing abnormalities may contribute to S1 response deficits, standard and rare (15% probability) paired stimuli were presented to 21 participants with schizophrenia and 22 healthy controls. P50 and N100 ERP amplitude as well as low, beta and gamma frequency power were measured to examine the time course and relative contributions of oscillatory activity affecting auditory processing in schizophrenia. In this study, schizophrenia patients exhibited less evoked beta 1 power (12-20 Hz) in response to salient stimuli at S1, and lower N100 amplitude in response to all S1 stimuli. No group differences were found in the low, beta 2 (20-30 Hz), or gamma frequency ranges. These findings suggest aberrant sensory processing during stages of stimulus evaluation and saliency detection in schizophrenia.

Sensory gating impairments in heavy cannabis users are associated with altered neural oscillations.

Central cannabinoid receptors mediate neural oscillations and are localized to networks implicated in auditory P50 sensory gating, including the hippocampus and neocortex. The current study examined whether neural oscillations evoked by the paired clicks (S1, S2) are associated with abnormal P50 gating reported in cannabis users. Seventeen heavy cannabis users and 16 cannabis naïve controls participated. Analyses included P50 amplitudes, and time-frequency analyses (event-related spectral perturbations, ERSPs; intertrial coherence, ITC). Consistent with prior studies, cannabis users exhibited reduced P50 gating. The ERSP analysis yielded attenuated high frequency activity in the beta range (13-29 Hz) post-S1 and in the gamma range (30-50 Hz) post-S2 in the cannabis group, compared with the control group. Greater levels of cannabis use were positively associated with high P50 ratios and negatively with post-S2 ERSP gamma power. Findings suggest that heavy cannabis use is associated with aberrant beta and gamma activity in the dual-click procedure, which corroborates recent work demonstrating disruption of beta/gamma by cannabinoid receptor (CB1) agonists in a rat analogue of this task and highlights the translational potential of the dual-click procedure [corrected]

Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia.

Theoretical models suggest that symptoms of schizophrenia may be due to a dysfunctional modulatory system associated with the cerebellum. Although it has long been known that the cerebellum plays a critical role in associative learning and motor timing, recent evidence suggests that it also plays a role in nonmotor psychological processes. Indeed, cerebellar anomalies in schizophrenia have been linked to cognitive dysfunction and poor long-term outcome. To test the hypothesis that schizophrenia is associated with cerebellar dysfunction, cerebellar-dependent, delay eye-blink conditioning was examined in 62 individuals with schizophrenia and 62 age-matched non-psychiatric comparison subjects. The conditioned stimulus was a 400 ms tone, which co-terminated with a 50 ms unconditioned stimulus air puff. A subset of participants (25 with schizophrenia and 29 controls) also completed the Wechsler Abbreviated Scale of Intelligence. Participants with schizophrenia exhibited lower rates of eye-blink conditioning, including earlier (less adaptively timed) conditioned response latencies. Cognitive functioning was correlated with the rate of conditioned responsing in the non-psychiatric comparison subjects but not among those with schizophrenia, and the magnitude of these correlations significantly differed between groups. These findings are consistent with models of schizophrenia in which disruptions within the cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are postulated to underlie the cognitive fragmentation that characterizes the disorder.

Pre-attentive auditory processing in ultra-high-risk for schizophrenia with magnetoencephalography.

BACKGROUND: It is uncertain whether the neurobiological abnormalities in schizophrenia emerge at the first episode of the disorder or are present during the prodromal phase. Recent neuroimaging studies indicate that some brain abnormalities are present in subjects at ultra-high-risk (UHR) for schizophrenia. Pre-attentive auditory deficits, which represent a core feature of schizophrenia, were investigated in individuals at UHR for schizophrenia. METHODS: We assessed early auditory processing indexed by the magnetoencephalographic mismatch negativity magnetic counterpart (MMNm) component elicited during a passive oddball paradigm in UHR individuals. Sixteen individuals at UHR for schizophrenia on the basis of clinical criteria and 18 healthy control subjects matched for age, gender, and education participated. A duration-deviant oddball paradigm was used to obtain MMNm dipole moment, which was measured with cortical source modeling. RESULTS: The UHR group showed a smaller right MMNm dipole moment than those of the control group. Group difference was observed in MMNm dipole latency, suggestive of slowed processing. The left MMNm dipole moment was negatively correlated with clinical symptoms measured by the Comprehensive Assessment of At-Risk Mental States positive symptom score. CONCLUSIONS: Our findings suggest that deficits in the early stage of auditory processing in individuals at UHR for schizophrenia exist before the onset of psychosis. The MMNm dipole moment might reflect the functional decline at the prodromal stage of schizophrenia.

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction.

OBJECTIVES: Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD. METHODS: Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls. RESULTS: Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses. CONCLUSIONS: These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.