Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia
Introduction
Accumulating theoretical and empirical evidence suggests that schizophrenia may be associated with a fundamental disturbance in the timing of neural processes (Andreasen et al., 1998, Friston, 1998, Green and Nuechterlein, 1999, Tononi and Edelman, 2000, Bressler, 2003, Paulus and Braff, 2003, Andreasen and Pierson, 2008). This putative deficit in the temporal coordination of information processing in the brain, sometimes referred to as cognitive dysmetria (Andreasen et al., 1998, Andreasen and Pierson, 2008), may lead to disturbances of consciousness as well as poor coordination of perceptual, affective, cognitive, and motor processes.
Although the cerebellum has traditionally been viewed as primarily responsible for the coordination of voluntary movement, gait, and posture, compelling evidence is accumulating that it also may play a role in a wide variety of psychological functions – including cognitive and affective processes (e.g., Ivry and Keele, 1989, Leiner et al., 1993, Schmahmann and Sherman, 1998, Schmahmann, 2001a, Schmahmann, 2001b, Katz and Steinmetz, 2002, Schmahmann, 2004). The cerebellum is an especially important target of study in schizophrenia because abnormalities in a cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are a possible source of anomalies in the fluidity of behavior across time in the disorder (Andreasen et al., 1998, Andreasen and Pierson, 2008). A variety of cerebellar structural anomalies have been observed in schizophrenia, some of which have been associated with cognitive deficits, clinical symptoms, and outcomes (Nopoulos et al., 1999, Wassink et al., 1999, Ichimiya et al., 2001, Ho et al., 2004, Okugawa et al., 2006), providing further support for the cognitive dysmetria theory of schizophrenia (Andreasen, 1999). However, results to the contrary have also been reported (Wang et al., 2003).
Although results from these structural studies offer support for the theory that cerebellar abnormalities contribute to cognitive dysmetria in schizophrenia (Andreasen and Pierson, 2008, Andreasen, 1999), very little is known about the functional integrity of the cerebellum in the disorder nor is much known about neural mechanisms that may provide valuable insight into the known functional deficits in schizophrenia. The evidence that schizophrenia is associated with cerebellar abnormalities is especially interesting given that the cerebellum appears to play a fundamental role in the timing of neural processes associated with not only response timing (e.g., Ivry et al., 1988, Ivry and Keele, 1989, Fiala et al., 1996, Steinmetz, 2000, Spencer et al., 2003), but also perceptual, and cognitive functioning (e.g., Ivry and Keele, 1989, Leiner et al., 1991, Katz and Steinmetz, 2002). For example, the cerebellum has been implicated in a variety of cognitive domains, including working memory and executive control, inner speech, attention, mental imagery, and emotion (see Baillieux et al., 2008, for review). Moreover, patients with cerebellar lesions show deficits in timing tasks (Ivry et al., 1988, Ivry and Keele, 1989) and sometimes exhibit symptoms that are remarkably similar to those seen in schizophrenia, including impaired visuospatial memory, blunted affect or disinhibited, contextually inappropriate behavior, impaired executive function, and inattention (Schmahmann and Sherman, 1997, Schmahmann and Sherman, 1998).
The potential importance of the cortico-cerebellar-thalamic-cortical circuit (CCTCC) in schizophrenia is further underscored by the fact that feedback and feedforward loops are widely known to connect the cerebellum with areas of the brain implicated in the disorder, including the thalamus, limbic system (Anand et al., 1959, Snider et al., 1976), and prefrontal cortex (Schmahmann and Pandya, 1995). Taken together, these findings and the connectivity of the cerebellum with brain areas affected in schizophrenia implicate cerebellar dysfunction in the disorder. However, despite the evidence supporting the CCTCC model of schizophrenia, the specific functional abnormalities of the cerebellum in schizophrenia are unclear. This lack of knowledge was an impetus for this study of cerebellar-dependent eye-blink conditioning (EBC) in schizophrenia.
The neural circuitry associated with EBC is distinct and well characterized. While structures besides the cerebellum modulate CR acquisition and performance in the delay version of EBC (e.g., the amygdala, septum, and hippocampus; Christian and Thompson, 2003), only the cerebellum is critical for performance in short interval, delay classical EBC (Lavond, 1993, Kim and Thompson, 1997, Christian and Thompson, 2003, Steinmetz, 2000). Furthermore, the magnitude of conditioning is related to the morphology and volume of the cerebellum in humans (Woodruff-Pak et al., 2000) and, thus, could be altered by structural anomalies observed in schizophrenia. Consistent with the theoretical and empirical evidence of a role for the cerebellum in neural timing and psychological processes, functional abnormalities in cerebellar-mediated EBC have been reported in psychiatric disorders with cognitive, perceptual, and affective symptoms, including bipolar disorder (Bolbecker et al., 2008) and schizophrenia (Spain, 1966, Sears et al., 2000, Hofer et al., 2001, Marenco et al., 2003, Brown et al., 2005). However, the specific nature of delay EBC findings in schizophrenia has been contradictory in the smaller patient groups studied to date. Impaired acquisition has been reported (Hofer et al., 2001, Brown et al., 2005) while other studies have reported no differences (Marenco et al., 2003) or facilitated conditioning (Spain, 1966, Sears et al., 2000). In addition, both longer (Marenco et al., 2003) and shorter (Brown et al., 2005) response onset and peak latencies have been reported. Because these conflicting results may be due to insufficient sample sizes or methodological differences, this study was undertaken to further characterize EBC in schizophrenia.
Given that the cerebellum is critical for the acquisition and timing of EBC (Steinmetz, 2000) and the cognitive dysmetria model posits that cerebellar abnormalities are related to cognitive deficits in schizophrenia (Andreasen et al., 1998, Andreasen and Pierson, 2008), EBC deficits may be associated with cognitive performance in schizophrenia. In healthy people, cerebellar volume is positively correlated with both intelligence (Andreasen et al., 1993, Paradiso et al., 1997) and the magnitude of eye-blink conditioning (Woodruff-Pak et al., 2000). However, to our knowledge, neuropsychological correlates of EBC in schizophrenia have not been explored. Hence, a secondary goal of this study was to examine the relationship between intelligence and EBC in schizophrenia.
The present paper reports findings from a large sample of schizophrenia patients (N = 62) and age-matched controls (N = 62). The major hypothesis, based on empirical and theoretical evidence, was that the schizophrenia group would manifest impaired learning (i.e. fewer conditioned responses) and abnormally timed conditioned responses (i.e. earlier response latencies). In addition, a subset of participants underwent neuropsychological testing. We predicted that cognitive performance would be positively correlated with conditioned response acquisition.
Section snippets
Participants
Participants were 62 individuals (23 women) with DSM-IV schizophrenia and 62 age-matched non-psychiatric healthy controls (32 women). Controls were matched to a corresponding schizophrenia participant if their ages were within 2 years of each other. Diagnostic status was determined using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) sections for mood disorders, psychotic disorders, and substance abuse disorders, and chart review. Symptom severity was assessed using the
Characterization of raw EMG data
The grand averaged EMG data from all paired conditioning trials are plotted by group in Fig. 1. A temporal schematic of the relationship between the tone CS and air puff US is shown below the x-axis. The boxed inset contains the CR window, which is followed in the main figure by a prominent deflection; this large amplitude deflection is the unconditioned blink response to the air puff. These averaged raw data illustrate that schizophrenia was associated with less EMG activity in the conditioned
Discussion
The current findings are notable because of the clear impairment in cerebellar-dependent eye-blink conditioning in the schizophrenia group and the large sample size. Impairment in the functional integrity of the cerebellum and associated brainstem circuits that support eye-blink conditioning was indicated by two primary findings. First, the schizophrenia group produced significantly fewer conditioned responses; second, when conditioned responses were produced, they were timed unusually early
Role of funding of source
Funding for this study was provided by an NIMH R01 Grant (MH074983- 01) awarded to WPH and a NARSAD Young Investigator Award to WPH. Neither NIMH nor NARSAD had further roles in the study design, collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Contributors
Amanda R. Bolbecker and William P. Hetrick designed the study and analyzed the data, as well as wrote the main drafts of the manuscript. Chrystal Mehta and Chad R. Edwards assisted in the data processing and figure construction. Joseph E. Steinmetz and Brian F. O'Donnell contributed to the critical interpretation of results. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors have no conflicts of interest to report related to the present report.
Acknowledgments
We would like to thank the clinical research team at Larue D. Carter Memorial Hospital and the Indiana University Neuroscience Clinical Research Center for their support. We are especially grateful to Ashley Steffen, Misty Bodkins, Jennifer Boggs, Sam Kaiser, and Colleen Merrill for their assistance in the assessment and diagnosis of participants and in collecting eye-blink conditioning data.
References (68)
- et al.
The role of the cerebellum in schizophrenia
Biol. Psychiatry
(2008) - et al.
Cerebellar neurocognition: insights into the bottom of the brain
Clin. Neurol. Neurosurg.
(2008) - et al.
Eye-blink conditioning deficits indicate timing and cerebellar abnormalities in schizophrenia
Brain Cogn.
(2005) - et al.
Cerebellar synaptic protein expression in schizophrenia
Neuroscience
(2001) - et al.
Cerebellum volume and eye-blink conditioning in schizophrenia
Psychiatry Res.
(2008) The disconnection hypothesis
Schizophr. Res.
(1998)- et al.
Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses
Neuropharmacology
(1998) - et al.
Cerebellar dysfunction in neuroleptic naïve schizophrenia patients: clinical, cognitive, and neuroanatomic correlates of cerebellar neurologic signs
Biol. Psychiatry
(2004) - et al.
Impaired conditional discrimination learning in schizophrenia
Schizophr. Res.
(2001) - et al.
Reduced volume of the cerebellar vermis in neuroleptic-naïve schizophrenia
Biol. Psychiatry
(2001)
Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning
Trends Neurosci.
The human cerebrocerebellar system: its computing, cognitive, and language skills
Behav. Brain Res.
Cognitive and language functions of the human cerebellum
Trends Neurosci.
Single-cue delay and trace classical conditioning in schizophrenia
Biol. Psychiatry
An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept
Biol. Psychiatry
Neural disorganization in the superior cerebellar peduncle and cognitive abnormality in patients with schizophrenia: a diffusion tensor imaging study
Prog. Neuro-psychopharmacol. Biol. Psychiatry
Chaos and schizophrenia: does the method fit the madness?
Biol. Psychiatry
Cerebellar vermis in schizophrenia
Lancet
Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling
Neuroimage
Prefrontal cortex projections to the basilar pons: implications for the cerebellar contribution to higher function
Neurosci. Lett.
Cerebellar cognitive affective syndrome
Int. Rev. Neurobiol.
Cerebellar functional abnormalities in schizophrenia are suggested by classical eye-blink conditioning
Biol. Psychiatry
Cerebellar pathways to ventral midbrain and nigra
Exp. Neurol.
Brain substrates of classical eye-blink conditioning: a highly localized but also distributed system
Behav. Brain Res.
Schizophrenia and the mechanisms of conscious integration
Brain Res. Rev.
A diffusion tensor imaging study of middle and superior cerebellar peduncle in male patients with schizophrenia
Neurosci. Lett.
Cerebellar morphology as a predictor of symptoms and psychosocial outcome in schizophrenia
Biol. Psychiatry
Cerebellar projections to limbic system
J. Neurophysiol.
A unitary model of schizophrenia: Bleuler's “fragmented phrene” as schizencephaly
Arch Gen Psychiatry
Intelligence and brain structure in normal individuals
Am. J. Psychiatry
“Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry?
Schizophr. Bull.
Eye-blink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction
Bipolar Disord.
Secretin effects on cerebellar-dependent motor learning in schizophrenia
Am. J. Psychiatry
Cortical coordination dynamics and the disorganization syndrome in schizophrenia
Neuropsychopharmacology
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