Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia

Abstract

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.

Figure 1

Grand averaged trial-by-trial EMG data for all trials for the healthy control (upper panel) and schizophrenia (lower panel) subjects. The 400 ms conditioned stimulus (CS) co-terminates with the 50 ms (10psi) air puff. Both groups developed conditioned responses (CRs) as the experiment progressed, as can be seen in the period just prior to unconditioned stimulus (US) onset (indicated by the boxed inset), but the schizophrenia group exhibited fewer and more poorly timed CRs compared to controls.

Figure 2

Block averages derived from the grand averaged trial-by-trial EMG data shown. Single traces represent CR activity for each of the 10 trial blocks, with data from the healthy control participants shown in the left panel and data from the schizophrenia group in the right panel. CR amplitude and timing are more robust and consistent by the end of the experiment in the control group as compared to the schizophrenia group.

Figure 3

Mean ± SE across blocks for CR and UR primary dependent variables. (A) Comparison of Percent CRs for schizophrenia and healthy control groups. Both groups showed evidence of learning, as indicated by an increase in CR incidence as the experiment progressed, but the schizophrenia group had fewer CRs throughout the experiment. (B) Comparison of CR Peak Latency for schizophrenia group compared to healthy controls. Schizophrenia patients had faster CR latencies than healthy controls, indicating less adaptively timed responses. (C) Comparison of UR peak amplitude for healthy control and schizophrenia groups. Amplitude decreased for both groups as the experiment progressed, but the schizophrenia group had larger amplitudes compared to the healthy control group. (D) UR peak latency across blocks in schizophrenia and healthy control groups. UR latency decreased for both groups with experience, but the schizophrenia group had significantly slower UR latencies.

Figure 4

Scatter plots showing the relationships between IQ and conditioning in healthy controls (left) and in schizophrenia (right).