Emotion deficits in schizophrenia: timing matters

The past two decades of research on emotional response in schizophrenia has demonstrated that people with schizophrenia do not have a marked deficit in reported emotional experience in the presence of emotionally evocative stimuli. However, the extent to which people with schizophrenia maintain their emotional state to guide future behavior remains a largely unexplored area of investigation. In the present study, we tested hypotheses about whether people with schizophrenia maintained their emotional state in the absence of emotionally evocative stimuli. In addition to reported emotional experience, we measured startle response magnitude both during the viewing and after the offset of emotional pictures to assess whether people with schizophrenia (n = 31) and without schizophrenia (n = 28) differ in their patterns of immediate response to emotional pictures and in their patterns of maintenance of these responses. Our findings indicated that people with and without schizophrenia did not differ in their self-report or startle response magnitude during presentation of emotional pictures. However, healthy controls maintained these responses after the stimuli were removed from view, but people with schizophrenia did not.     

Motivational deficits in schizophrenia relate to abnormalities in cortical learning rate signals

Individuals from across the psychosis spectrum display impairments in reinforcement learning. In some individuals, these deficits may result from aberrations in reward prediction error (RPE) signaling, conveyed by dopaminergic projections to the ventral striatum (VS). However, there is mounting evidence that VS RPE signals are relatively intact in medicated people with schizophrenia (PSZ). We hypothesized that, in PSZ, reinforcement learning deficits often are not related to RPE signaling per se but rather their impact on learning and behavior (i.e., learning rate modulation), due to dysfunction in anterior cingulate and dorsomedial prefrontal cortex (dmPFC). Twenty-six PSZ and 23 healthy volunteers completed a probabilistic reinforcement learning paradigm with occasional, sudden, shifts in contingencies. Using computational modeling, we found evidence of an impairment in trial-wise learning rate modulation (α) in PSZ before and after a reinforcement contingency shift, expressed most in PSZ with more severe motivational deficits. In a subsample of 22 PSZ and 22 healthy volunteers, we found little evidence for between-group differences in VS RPE and dmPFC learning rate signals, as measured with fMRI. However, a follow-up psychophysiological interaction analysis revealed decreased dmPFC-VS connectivity concurrent with learning rate modulation, most prominently in individuals with the most severe motivational deficits. These findings point to an impairment in learning rate modulation in PSZ, leading to a reduced ability to adjust task behavior in response to unexpected outcomes. At the level of the brain, learning rate modulation deficits may be associated with decreased involvement of the dmPFC within a greater RL network.     

Eyeblink conditioning in rats using pontine stimulation as a conditioned stimulus

Previous studies using rabbits and ferrets found that electrical stimulation of the pontine nuclei or middle cerebellar peduncle could serve as a conditioned stimulus (CS) in eyeblink conditioning (Bao, Chen, & Thompson, 2000; Hesslow, Svensson, & Ivarsson, 1999; Steinmetz, 1990; Steinmetz, Lavond, & Thompson, 1985; 1989; Steinmetz et al., 1986; Tracy, Thompson, Krupa, & Thompson, 1998). The current study used electrical stimulation of the pontine nuclei as a CS to establish eyeblink conditioning in rats. The goals of this study were to develop a method for directly activating the CS pathway in rodents and to compare the neural circuity underlying eyeblink conditioning in different mammalian species. Rats were given electrical stimulation through a bipolar electrode implanted in the pontine nuclei paired with a periorbital shock unconditioned stimulus (US). Paired training was followed by extinction training. A subset of rats was given a test session of paired training after receiving an infusion of muscimol into the anterior interpositus nucleus. Rats given paired presentations of the stimulation CS and US developed CRs rapidly and showed extinction. Muscimol infusion prior to the test session resulted in a reversible loss of the eyeblink CR. The results demonstrate that electrical stimulation of the pontine nuclei can be used as a CS in rodents and that the CS pathway is similar in rats, rabbits, and ferrets. In addition, the loss of CRs following muscimol inactivation shows that the conditioning produced with pontine stimulation depends on cerebellar mechanisms.     

Eyeblink conditioning and systems consolidation: an ironic yet powerful pairing

Systems consolidation involves a prolonged process of memory reorganization that appears to be distinctly related to declarative memory. Declarative memory can be sharply contrasted with simple delay eyeblink classical conditioning, a prototypical example of nondeclarative memory. Yet inserting a trace interval between the conditioned and unconditioned stimuli endows eyeblink (trace) conditioning with many features of declarative memory. Work in humans has established that trace conditioning requires declarative memory. Recently trace eyeblink conditioning in animals has become one of the most powerful methods to study systems consolidation. Thus, it is ironic that a substantially nondeclarative form of memory has been so instructive concerning the organization of declarative memory.     

Speech motor deficits in cerebellar infarctions

Functional imaging studies demonstrated cerebellar activation during speech movements in the rostral cerebellar region. Ischemic lesions of this area, which is supplied by the superior cerebellar artery, induce dysarthria.     

Verbal processing deficits in schizophrenia

The authors reported that a subgroup of schizophrenic patients performed well on a tone serial position task but was impaired on an auditory word serial position task (Wexler, Stevens, Bowers, Cerniak, & Goldman-Rakic, 1998). This study assessed 30 schizophrenic and 32 controls (matched for comparable tone discrimination) on 4 versions of the verbal serial position tasks and 2 tone serial position tasks. Patients performed poorly on all verbal tasks but performed comparably to controls when tones served as stimuli. Proactive interference and visual presentation further compounded the verbal deficits. Deficits persisted with pronounceable nonword stimuli. These findings provide evidence of specific deficits in language-related processing, although the authors could not rule out the possibility that the differential effects that were observed between the tone and word tasks, and particularly among the verbal tasks, may result from differing discriminating power of the different tests.     

Autobiographical memory deficits in schizophrenia

This study investigated autobiographical memory processes in a group of individuals diagnosed with schizophrenia and matched controls. The schizophrenia group displayed an overgeneral style of autobiographical memory retrieval on two widely used measures, and displayed problems retrieving both autobiographical facts and events. They showed a specific impairment in the recall of autobiographical events and facts in early adulthood, around the time of onset of their illness. Retrieval deficits were independent of mood state and premorbid intellectual functioning. The magnitude of the deficits in autobiographical memory retrieval specificity were considerably greater than any general impairments in episodic and working memory.     

Word production deficits in schizophrenia

Fronto-cerebellar circuitry is implicated in word production. Data suggest that the cerebellum is involved in word search, whereas the prefrontal cortex underlies the selection of words from among competing alternatives. We explored the role of search and selection processes in word production deficits in schizophrenia patients. In Experiment 1, patients were impaired in a verb generation task under both high and low selection conditions but were more impaired in the high selection condition. In Experiment 2, when the difficulty level of search and selection conditions was equated in a word stem completion task, patients were only impaired in the search condition. Word search deficits underlie word production problems in schizophrenia, and may involve fronto-cerebellar dysfunction.     

Comparison of timing and classical conditioning

Four experiments with rats investigated if the timing of a stimulus (sound) correlated with the strength of a conditioned response (CR) to the stimulus. The timing (effective duration) of the stimulus was measured using the peak procedure, similar to a discrete-trials fixed-interval procedure. The rats were trained so that their response rate reached a maximum about 40 s or 60 s after the onset of a light; the time of the maximum measured from the start of the light (peak time) was the measure of timing. On some trials, the light was preceded by a short (5 s) or long (20 s or 30 s) interval of sound. We assumed that the difference in peak time after long and short sounds reflected the timing of the sound--if the sound was timed, the longer sound would produce a lower peak time; if the sound was not timed, the two durations of sound would produce the same peak time. The CR was lever-pressing during the sound. The sound was treated in various ways: presented alone (Experiments 1, 3, and 4), followed by food (Experiments 1, 3, and 4), preceded by food (Experiment 3), and followed by food after 20 s (Experiment 4). Treatments that produced no timing of sound produced no CR, and treatments that increased (or diseased) timing also increased (or decreased) the CR. The results suggest that there is overlap between the mechanisms that produce time discrimination and the mechanisms that produce classical conditioning.     

Affective deficits and pain insensitivity in schizophrenia

Affective deficits have long been considered a prominent feature of schizophrenia and play a central role in recent theory and research on the pathophysiology of this disorder. However, it has recently been argued that current approaches to the conceptualization and assessment of affective flattening in schizophrenia are confounded by the social and neuromotor deficits that are also prevalent in this disorder. Insensitivity to pain in individuals with schizophrenia — a phenomenon that has been reported frequently but never systematically investigated — provides one approach to examining affective flattening unconfounded by social and neuromotor deficits. Two studies are described in which signal detection theory measures of thermal pain sensitivity were examined in patients with schizophrenia, mood disorder, and normal controls; in addition, in the patients with schizophrenia, the relationships between these measures and measures of affective deficits were examined. Patients with schizophrenia had significantly poorer sensory discrimination of painful thermal stimuli than control subjects, but did not differ from controls with respect to their response criterion for reports of pain; patients with mood disorder had a significantly higher (i.e., more stoical) criterion for reports of pain than controls. As predicted, among the patients with schizophrenia, higher response criterion was significantly correlated with greater affective flattening and less intense affective experience (as well as with fewer positive symptoms and poorer premorbid adjustment). The results of these studies suggest that pain insensitivity in schizophrenia may reflect affective as well as sensory abnormalities, and that pain insensitivity in schizophrenia may provide a method for studying affective flattening in this disorder that is relatively independent of the social and neuromotor deficits that confound existing measures of this symptom. Continued examination of the relationship between pain insensitivity and affective deficits in schizophrenia is also important because numerous clinical reports have suggested that pain insensitivity is detrimental to health and can have life-threatening consequences in individuals with this disorder.This research was supported, in part, by research grants from the National Institute of Neurological Disorders and Stroke to Robert H. Dworkin (NS-30714) and W. Crawford Clark (NS-09263, NS-20248).     

Eyeblink classical conditioning and interpositus nucleus activity are disrupted in adult rats exposed to ethanol as neonates

Neonatal exposure to ethanol in rats, during the period of brain development comparable to that of the human third trimester, produces significant, dose-dependent cell loss in the cerebellum and deficits in coordinated motor performance. These rats are also impaired in eyeblink conditioning as weanlings and as adults. The current study examined single-unit neural activity in the interpositus nucleus of the cerebellum in adults following neonatal binge ethanol exposure. Group Ethanol received alcohol doses of 5.25 g/kg/day on postnatal days 4–9. Group Sham Intubated underwent acute intragastric intubation on postnatal days 4–9 but did not receive any infusions. Group Unintubated Control (from separate litters) did not receive any intubations. When rats were 3–7 mo old, pairs of extracellular microelectrodes were implanted in the region of the interpositus nucleus. Beginning 1 wk later, the rats were given either 100 paired or 190 unpaired trials per day for 10 d followed by 4 d of 100 conditioned stimulus (CS)-alone trials per day. As in our previous study, conditioned response acquisition in Group Ethanol rats was impaired. In addition, by session 5 of paired acquisition, Group Sham Intubated and Group Unintubated Control showed significant increases in interpositus nucleus activity, relative to baseline, in the CS–unconditioned stimulus interval. In contrast, Group Ethanol failed to show significant changes in interpositus nucleus activity until later in training. These results indicate that the disruption in eyeblink conditioning after early exposure to ethanol is reflected in alterations in interpositus nucleus activity.     

Identification of tone duration, line length, and letter position: an experimental approach to timing and working memory deficits in schizophrenia

Patients with schizophrenia display numerous cognitive deficits, including problems in working memory, time estimation, and absolute identification of stimuli. Research in these fields has traditionally been conducted independently. We examined these cognitive processes using tasks that are structurally similar and that yield rich error data. Relative to healthy control participants (n = 20), patients with schizophrenia (n = 20) were impaired on a duration identification task and a probed-recall memory task but not on a line-length identification task. These findings do not support the notion of a global impairment in absolute identification in schizophrenia. However, the authors suggest that some aspect of temporal information processing is indeed disturbed in schizophrenia.     

Hemispheric processing deficits in patients with paranoid schizophrenia

The purpose of the present study was to investigate hemispheric deficits in individuals with paranoid schizophrenia on four kinds of tasks: dichoptic viewing tasks involving verbal and nonverbal visual stimuli, and dichotic listening tasks involving verbal and nonverbal auditory stimuli. As dependent measures, both accuracy and speed of (correct) responding were measured. The sample recruited for this study consisted of 18 patients with paranoid schizophrenia, 15 outpatients with anxiety disorders, and 20 controls with no history of psychiatric disorders. Results indicated that, relative to the controls, the paranoid schizophrenic patients were less accurate and less efficient on auditory-verbal tasks requiring right hemisphere processing. Unlike the controls the paranoid schizophrenic patients manifested a lateralized left hemisphere advantage.     

Visuospatial attention in schizophrenia: deficits in broad monitoring

Although selective attention is thought to be impaired in people with schizophrenia (PSZ), prior research has found no deficit in the ability to select one location and withdraw attention from another. PSZ and healthy control subjects (HCS) performed a stimulus detection task in which one, two, or all four peripheral target locations were cued. When one or two locations were cued, both PSZ and HCS responded faster when the target appeared at a cued than uncued location. However, increases in the number of validly cued locations had much more deleterious effects on performance for PSZ than HCS, especially for targets of low contrast whose detection was more dependent on attention. PSZ also responded more slowly in trials with four cued locations relative to trials with one or two invalidly cued locations. Thus, visuospatial attention deficits in schizophrenia arise when broad monitoring is required rather than when attention must be focused narrowly.     

Declarative memory deficits and schizophrenia: problems and prospects

Cognitive deficits are among the most important factors leading to poor functional outcomes in schizophrenia, with deficits in declarative memory among the largest and most robust of these. Thus far, attempts to enhance cognition in schizophrenia have shown only modest success, which underlies increasing efforts to develop effective treatment strategies. This review is divided into three main parts. The first section delineates the nature and extent of the deficits in both patients with schizophrenia and in their adult, non-psychotic relatives. The second part focuses on structural and functional abnormalities in the hippocampus, both in people with schizophrenia and in animal studies that model relevant features of the illness. The third section views problems in declarative memory and hippocampal function from the perspective of elevated rates of common medical disorders in schizophrenia, with a focus on insulin insensitivity/diabetes. The likelihood that poor glucose regulation/availability contribute to declarative memory deficits and hippocampal abnormalities is considered, along with the possibility that schizophrenia and poor glucose regulation share common etiologic elements, and with clinical implications of this perspective for enhancing declarative memory.     

Motor timing deficits in children with Attention-Deficit/Hyperactivity disorder

Children with Attention-Deficit/Hyperactivity Disorder (ADHD) are thought to have fundamental deficits in the allocation of attention for information processing. Furthermore, it is believed that these children possess a fundamental difficulty in motoric timing, an assertion that has been explored recently in adults and children. In the present study we extend this recent work by fully exploring the classic Wing and Kristofferson (1973) analysis of timing with typically developing children (n=24) and children with ADHD (n=27). We provide clear evidence that not only do children with ADHD have an overall timing deficit, they also time less consistently when using a similar strategy to typically developing children. The use of the Wing and Kristofferson approach to timing, we argue, will result in the discovery of robust ADHD-related timing differences across a variety of situations.