Cerebellar functional abnormalities in schizophrenia are suggested by classical eyeblink conditioning.

BACKGROUND: Previous research suggests that schizophrenia may result from disruptions in a cortico-cerebellar-thalamic-cortical circuit (CCTCC) producing a mental incoordination or "cognitive dysmetria." To further evaluate the cerebellar contribution to this disrupted circuitry, medication-free patients with schizophrenia completed classical eyeblink conditioning, a cerebellar-mediated learning task. METHODS: For classical eyeblink conditioning, 70 trials with a tone conditioned stimulus (CS) and air puff unconditioned stimulus (US) were presented to 15 patients with schizophrenia and 15 healthy control subjects. Acquisition rate for the conditioned response (CR) and response timing were compared between the two groups. RESULTS: Patients with schizophrenia displayed facilitated conditioning compared to control subjects based on a greater number of CRs during the session and a faster acquisition of the learned response. CONCLUSIONS: Facilitated conditioning suggests that an enhanced excitability in the cerebellum occurs as part of a disrupted CCTCC in schizophrenia. The enhanced cerebellar-mediated associative learning may be maladaptive in the context of normal cerebro-cerebellar interactions, leading to the characteristic motor and mental incoordination of the disorder. Classical eyeblink conditioning may provide a useful model system for studying cerebellar involvement in the pathogenesis and treatment of schizophrenia.

An MRI study of the basal ganglia in autism.

1. High-resolution MRI scans were obtained from 35 relatively high-functioning persons with autism and 36 healthy controls, comparable in age, gender, and IQ. 2. Volumetric measurements were obtained from manual tracing of the bilateral caudate, putamen, and globus pallidus. 3. An increased volume of the caudate nuclei was found in subjects with autism. Caudate enlargement was proportional to increased total brain volume in subjects with autism. 4. Caudate volume was associated with compulsions and rituals, difficulties with minor change, and complex motor mannerisms in autism. 5. Based on evidence of caudate abnormalities, a second MRI study was completed which replicated the finding of caudate enlargement in autism using an independent sample. 6. The caudate may be part of an abnormal distributed neural network in autism and involved in the ritualistic--repetitive behaviors of the disorder.

Effects of haloperidol on sensory processing in the hippocampus during classical eyeblink conditioning.

The rabbit classical eyeblink conditioning paradigm was used to assess the effects of haloperidol on hippocampal function. Haloperidol disrupted hippocampal activity and conditioned responses (CRs) at low but not high conditioned stimulus (CS) intensities. The observed relationship of hippocampal activity and the CR suggested that the hippocampus encoded sensory features associated with the learned response. Sensory processing by the hippocampus appeared to be altered by haloperidol through attenuation of the ability of a CS to evoke a learned response. Results are discussed in terms of the role of the hippocampus in sensory processing and possible mechanisms for the beneficial effects of haloperidol in schizophrenia. Classical eyeblink conditioning may provide a model system for studying behavioral and biological issues relevant to the etiology and treatment of schizophrenia.

Involvement of the ventrolateral thalamic nucleus in rabbit classical eyeblink conditioning.

The involvement of the ventrolateral nucleus of the thalamus in relaying learning-related activity to higher brain structures during classical conditioning of the rabbit eyelid response was examined in two experiments. In the first study, multiple-unit ventrolateral thalamic nucleus activity was monitored before and after lesions of either the cerebellar interpositus nucleus or red nucleus were given. Before the lesions were given, conditioned response-related activity was observed in the ventrolateral thalamic nucleus. Lesions of the interpositus nucleus, but not the red nucleus, disrupted the conditioning-related activity in the ventrolateral thalamic nucleus, thus suggesting that an efferent copy of conditioned response-related activity is projected directly from the interpositus nucleus to higher brain areas by way of the ventrolateral thalamic nucleus. In the second study, multiple unit activity in the hippocampus was monitored before and after lesions were placed in the ventrolateral thalamic nucleus or red nucleus. Conditioning-related activity in the hippocampus was not affected by either lesion, thus suggesting that maintenance of training-related activity in the hippocampus is not critically dependent on cerebellar information relayed through the ventrolateral thalamic nucleus or red nucleus.

Abnormal classical eye-blink conditioning in autism.

Cerebellar and limbic system pathologies have been reported in persons with autism. Because these brain areas are involved centrally in the acquisition and performance in classical eye-blink conditioning, this study evaluated conditioning in 11 persons with autism. Compared to matched controls, persons with autism learned the task faster but performed short-latency, high-amplitude conditioned responses. In addition, differences in learning the extinction rates systematically varied with age thus suggesting a developmental conditioning abnormality in autism. The observed pattern of eye-blink conditioning may indicate that persons with autism have the ability to rapidly associate paired stimuli but, depending on processing of certain contextual information, have impairments in modulating the timing and topography of the learned responses. This abnormality may relate to deviant cerebellar-hippocampal interactions. The classical eye-blink conditioning paradigm may provide a useful model for understanding the biological and behavioral bases of autism.

Possible CS and US pathways for rabbit classical eyelid conditioning: electrophysiological evidence for projections from the pontine nuclei and inferior olive to cerebellar cortex and nuclei.

Projections from the lateral region of the pontine nuclei and the dorsal accessory inferior olive to both cerebellar cortex and cerebellar dentate/interpositus nuclei were electrophysiologically examined using single-pulse stimulation and single-unit and population recording. Stimulation of the pontine nuclear region activated population potentials and single units recorded in both cerebellar cortex and deep nuclei. Pontine-evoked activity in cerebellar cortex (Larsell's lobule HVI and adjacent areas) was rather well-defined and strong while pontine-evoked activity in the deep cerebellar nuclei seemed relatively more diffuse and weaker. Short onset latencies for both single units and population potentials were found suggesting direct projections. Similar to previous studies, inferior olive stimulation evoked short-latency responses in cerebellar cortex and nuclei thus suggesting direct projections. More pontine- and olivary-evoked activity was seen in cortex than in the nuclei with slightly more olivary-evoked potentials per recording electrode penetration observed than pontine-evoked activity. Our findings suggest that cortical and nuclear regions of the cerebellum receive converging projections from the pontine nuclei and inferior olive, projections that may carry information about stimuli used during classical conditioning. These findings are discussed in terms of cerebellar circuits that may be involved in classical eyelid conditioning.

Cerebellar interpositus nucleus lesions disrupt classical nictitating membrane conditioning but not discriminative avoidance learning in rabbits.

Cerebellar interpositus nucleus lesions were given to 14 rabbits trained in two behavioral paradigms; discriminative avoidance conditioning of locomotor behavior and classical nictitating membrane conditioning. Bilateral lesions that prevented acquisition of the classically conditioned response on both the left and right side failed to affect the acquisition or performance of the conditioned discriminative avoidance response. The results are discussed in terms of differences in neural substrates that apparently subserve the two forms of learning.

Dorsal accessory inferior olive activity diminishes during acquisition of the rabbit classically conditioned eyelid response.

Eight rabbits were implanted with chronic recording electrodes in the rostromedial region of the dorsal accessory inferior olive (DAO). Multiple-unit DAO activity was recorded during 5 training sessions consisting of paired tone conditioned stimulus (CS) and air puff unconditioned stimulus (US) trials. Initially, the air puff US produced a large somatosensory-evoked response in the DAO during the paired CS-US presentations. As percent CRs increased across sessions, however, the DAO activity on paired trials decreased dramatically. In contrast, there were no significant decreases in DAO activity on US-alone trials presented at the end of each paired conditioning session. These results suggest that an associative process suppresses DAO activity during classical eyelid conditioning. Possible mechanisms of DAO inhibition and its involvement as part of the US 'reinforcement' pathway are discussed.

Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses.

The role of the cerebellum and the red nucleus in the conditioned eyeblink response was assessed, using a combination of reversible lesions and multiple-unit extracellular recording in the awake, behaving rabbit. Lesion, recording, and stimulation experiments have indicated that both of these structures are involved in the performance of learned skeletal muscle responses. The present study sought to distinguish the relative contributions of the interpositus nucleus and the red nucleus to the expression of the learned response by recording behavior-related multiple unit activity in one structure while reversibly inactivating the other via injections of local anesthetic. Results indicate that inactivating either the interpositus or the red nucleus temporarily abolishes the learned eyeblink response. Injection of lidocaine into the interpositus also abolishes the neuronal unit model of the conditioned response in the red nucleus, while injection into the red nucleus does not affect the model in the interpositus. These results are consistent with the hypothesis that the red nucleus acts as a relay for motor commands from the cerebellum, and that the plasticity that generates conditioned responses occurs in the cerebellum or an afferent structure.

Acquisition of classically conditioned-related activity in the hippocampus is affected by lesions of the cerebellar interpositus nucleus.

Rabbits were first given left cerebellar interpositus nucleus lesions followed by classical nictitating membrane (NM) conditioning using paired presentations of a tone conditioned stimulus and an air puff unconditioned stimulus. Multiple-unit hippocampal activity was monitored over the course of training. In rabbits with anterior interpositus lesions, the acquisition of learned responses and significant increases in training-related hippocampal activity were prevented when paired training was given to the left NM but not when training was switched to the right NM. Rabbits with lesions anterior to the interpositus or in surrounding cerebellar regions failed to show deficits in behavioral responding or hippocampal activity. These results indicate that acquisition of conditioning-related activity in the hippocampus depends on an intact interpositus nucleus of the cerebellum.

Haloperidol impairs classically conditioned nictitating membrane responses and conditioning-related cerebellar interpositus nucleus activity in rabbits.

Rabbits, chronically implanted with recording electrodes in the cerebellar interpositus nucleus and following acquisition of a classically conditioned eyelid response, were injected with haloperidol (HAL, 250 micrograms/kg). HAL significantly reduced the number of conditioned responses when a 75 and 85 dB tone conditioned stimulus (CS) was presented but not when a 95 dB tone CS was used. There was a corresponding decrease in interpositus activity at the 75 and 85 dB CS intensities but not at the 95 dB intensity. HAL appeared to disrupt CRs and interpositus activity by increasing the intensity threshold of the tone CS for eliciting conditioned responses. Possible mechanisms for the effect of HAL on neural circuitry involved in classical eyelid conditioning are discussed.