Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages

We previously reported that patients with schizophrenia failed to demonstrate normal sleep-dependent improvement in motor procedural learning. Here, we tested whether this failure was associated with the duration of Stage 2 sleep in the last quartile of the night (S2q4) and with spindle activity during this epoch. Fourteen patients with schizophrenia and 15 demographically matched controls performed a motor sequence task (MST) before and after a night of polysomnographically monitored sleep. Patients showed no significant overnight task improvement and significantly less than controls, who did show significant improvement. While there were no group differences in overall sleep architecture, patients showed significant reductions in fast sigma frequency power (45%) and in spindle density (43%) during S2q4 sleep at the electrode proximal to the motor cortex controlling the hand that performed the MST. Although spindle activity did not correlate with overnight improvement in either group, S2q4 sleep duration in patients significantly correlated with the plateau level of overnight improvement seen at the end of the morning testing session, and slow wave sleep (SWS) duration correlated with the delay in reaching this plateau. SWS and S2q4 sleep each predicted the initial level of overnight improvement in schizophrenia, and their product explained 77% of the variance, suggesting that both sleep stages are necessary for consolidation. These findings replicate our prior observation of reduced sleep-dependent consolidation of motor procedural learning in schizophrenia and link this deficit to specific sleep stages. They provide further evidence that sleep is an important contributor to cognitive deficits in schizophrenia.     

Effects of daytime naps on procedural and declarative memory in patients with schizophrenia

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Straight memory deficits and sleep disturbances are well-known in patients with schizophrenia. This study tested the hypothesis that patients with schizophrenia have a deficit in procedural and declarative memory consolidation after a short midday nap when compared to healthy controls and patients with remitted to moderate major depression.Following a normal night’s sleep, 22 healthy subjects, 20 patients with major depression and 21 patients with schizophrenia were studied in a napping and wake condition in a random-order cross-over design, early in the afternoon. To test declarative memory, the Rey-Osterrieth Complex Figure Test respectively the Taylor Complex Figure Test and, for procedural learning, a mirror tracing task were performed.The present study is the first to demonstrate significant differences between individuals with schizophrenia, depression and healthy matched controls with regard to measures of sleep and memory performance after a short period of daytime sleep (napping). In particular we found that a daytime nap of only about 40 min led to improvement of declarative memory performance in all investigated groups, whereas no beneficial effect was seen on procedural performance in the group of medicated patients with schizophrenia in contrast to healthy controls and patients with remitted to moderate major depression.     

The role of sleep in forgetting in temporal lobe epilepsy: a pilot study

The purpose of this study was to examine how sleep impacts memory function in temporal lobe epilepsy (TLE). Patients with TLE (n=7) and control subjects (n=9) underwent training and overnight testing on (1) a motor sequence task known to undergo sleep-dependent enhancement in healthy subjects, and (2) the selective reminding test, a verbal memory task on which patients with TLE have shown impaired performance 24 hours after training. Sleep data were collected by polysomnography. Results indicate that patients with TLE display greater forgetting on the selective reminding test compared with controls over 12 hours of daytime wakefulness, but not over a similar period including a night of sleep. Slow wave sleep is correlated with overnight performance change on the selective reminding test. Patients with TLE show no deficit in sleep-dependent motor sequence task improvement. The findings provide potential insight into the pattern and pathophysiology of forgetting in TLE.     

A double dissociation of memory impairments in major depression

Sleep benefits the consolidation of both declarative and nondeclarative memories, however the question if these two memory systems profit from sleep in more or less similar ways is still under debate. Studying the on-line and off-line consolidation of declarative and nondeclarative memory tasks in depressed patients and healthy controls, we here present a clear double dissociation between memory systems and consolidation phases, suggesting radically different ways how sleep benefits memory consolidation. 37 medicated inpatients with an acute episode of major depression and 31 healthy controls were assessed using a nondeclarative (sequential finger tapping) memory task before and after a night with polysomnography, 27 of the depressed and 22 of the control subjects additionally performed a declarative (paired associates) task. Although depressed patients and control subjects did not differ in practice-dependent learning of the nondeclarative motor task in the wake state, healthy subjects showed overnight improvements in tapping performance of 11.4%, while the patients' performance decreased overnight by 11.5%. This pattern was reversed for the declarative task: While patients learned 33.5% less word pairs than controls in the wake state, overnight changes did not differ between the two groups. These results suggest a double dissociation of memory consolidation processes in major depression: Off-line memory consolidation in major depression is impaired for nondeclarative, but not declarative tasks. The same tasks in the wake state show a reversed pattern, with performance in declarative but not nondeclarative tasks being impaired in major depression.     

First night of CPAP: impact on memory consolidation attention and subjective experience

ObjectiveNeurocognitive deficits are common and serious consequences of obstructive sleep apnea (OSA). Currently, the gold standard treatment is continuous positive air pressure (CPAP) therapy, although the clinical responses to this intervention can be variable. This study examined the effect of one night of CPAP therapy on sleep-dependent memory consolidation, attention, and vigilance as well as subjective experience.MethodsFifteen healthy controls and 29 patients with obstructive sleep apnea of whom 14 underwent a full-night CPAP titration completed the psychomotor vigilance test (PVT) and motor sequence learning task (MST) in the evening and the morning after undergoing overnight polysomnography. All participants also completed subjective evaluations of sleep quality.ResultsParticipants with OSA showed significantly less overnight improvement on the MST compared to controls without OSA, independent of whether or not they had received CPAP treatment, while there was no significant difference between the untreated OSA and CPAP-treated patients. Within the OSA group, only those receiving CPAP exhibited faster reaction times on the PVT in the morning. Compared to untreated OSA patients, they also felt subjectively more rested and reported that they slept better.ConclusionOur results demonstrate an instant augmentation of subjective experience and, based on PVT results, attention and vigilance after one night of CPAP, but a lack of an effect on offline sleep-dependent motor memory consolidation. This dissociation may be explained by different brain structures underlying these processes, some of which might require longer continued adherence to CPAP to generate an effect.     

Procedural learning in schizophrenia investigated with functional magnetic resonance imaging

A cerebral basis for the acquisition and retention of procedural knowledge in schizophrenia was examined with 1.5 T functional MRI during an embedded sequence Serial Reaction Time Task (SRTT) in 10 chronic medicated patients and 15 healthy controls. Comparable procedural learning was observed in both groups, suggesting that the impairment reported in previous schizophrenia samples may not be robust. Consistent with previous fMRI reports, procedural learning in the control group was associated with activity in the dorsal striatum, anterior cingulate, parietal cortex and frontal cortex. Greater procedural learning related activity was observed in the control relative to the schizophrenia group in the bilateral frontal, left parietal and bilateral caudate regions. Patients did not activate frontal or parietal areas while responding to the embedded sequence within the SRTT, but greater activation during procedural learning was observed relative to the control sample in the right anterior cingulate, left globus pallidus and the right superior temporal gyrus. Thus, despite comparable instantiation of procedural learning in schizophrenia, the cerebral activation associated with this cognitive skill was abnormal. The paucity of activity in bilateral frontal cortex, left parietal cortex and bilateral caudate nucleus may represent cerebral dysfunction associated with schizophrenia, whereas the hyperactivation of the right superior temporal gyrus, the right anterior cingulate cortex and the left globus pallidus may represent a compensatory cerebral action capable of facilitating near-normal task performance. The results are thus consistent with a neurodevelopmental pathology impinging on fronto-subcortical circuitry.     

Sleep improves sequential motor learning and performance in patients with prefrontal lobe lesions

OBJECTIVES: Motor skill learning involves both practice and a latent, sleep-dependent process of consolidation that develops after training ("off-line" learning). Sleep consolidation is linked to reduced brain activation in prefrontal areas, along with strong involvement of parietal regions. The objective in this study was to investigate the influence of sleep on the consolidation process of a motor task in patients with prefrontal damage. PATIENTS AND METHODS: For that purpose 14 patients with acquired focal prefrontal lesions, 15 age-matched healthy controls, and five patients with parietal lesions were evaluated on a serial reaction time task, SRTT, before and after a night of monitored sleep. Verbal and working memory was also tested. We anticipated that patients with prefrontal lesions, who are impaired in the acquisition of motor tasks, would benefit greater from sleep than the other two groups, since consolidation does not depend on prefrontal regions. RESULTS: Prefrontal patients showed an erratic learning curve at night, with great inter- and intrasubject variability that normalized after sleep. They also showed higher overnight learning of the motor skill and improvement on speed performance on the SRTT. No differences in the other memory tests were found between sessions. CONCLUSION: Prefrontal-injured patients benefit from night sleep in terms of motor task learning and performance, likely related to an advantageous off-line learning. Sleep could play a role in motor rehabilitation programs in prefrontal patients.     

Sleep-dependent memory consolidation of a new task is inhibited in psychiatric patients

Schizophrenic and depressive patients show impeded sleep-dependent procedural memory consolidation. But this has been shown mainly for tasks testing the adaptation of old skills. This study tested the overnight memory consolidation of a new task and the transfer of this new skill to a similar task. Using an adapted version of the sequential finger tapping task, keyboard-naïve Ethiopian depressive (n = 8) and schizophrenic (n = 15) patients and healthy controls (n = 11 and n = 17) were tested twice, 24 h apart. In addition the subjects underwent training in a second sequence after the retest of the first sequence. Both schizophrenic and depressive patients did not show a significant overnight change in performance (1% and 4% improvement respectively) in the task and differed significantly from the healthy control groups who did show significant improvement (16% and 22%). Further in contrast to the healthy controls both patients groups showed no significant transfer of the newly acquired skill to the second sequence. This study shows that depressive and schizophrenic patients are not only deficient in the overnight memory consolidation of a new task, but also fail to show a transfer of this new skill to similar tasks.     

The role of the orbitofrontal cortex in human discrimination learning

Several lines of evidence implicate the prefrontal cortex in learning but there is little evidence from studies of human lesion patients to demonstrate the critical role of this structure. To this end, we tested patients with lesions of the frontal lobe (n = 36) and healthy controls (n = 35) on two learning tasks: the weather prediction task (WPT), and an eight-pair concurrent visual discrimination task (‘Choose’). Performance of both tasks was previously shown to be disrupted in patients with Parkinson's disease; the Choose deficit was only present when patients were medicated. Patients with damage to the orbitofrontal cortex (OFC) were significantly impaired on Choose, compared to both healthy controls and non-OFC lesion patients. The OFC lesion patients showed a mild deficit on the first 50 trials of the WPT, compared to the control subjects but not non-OFC lesion patients. The selective deficit in the OFC patients on Choose performance could not be attributed to the larger lesion size in this group, and the deficit was not correlated with the volume of damage to adjacent prefrontal subregions (e.g. anterior cingulate cortex). These data support the notion that the OFC play a role in normal discrimination learning, and suggest qualitative similarities in learning performance of patients with OFC damage and medicated PD patients.     

Positive and negative spatial priming in schizophrenia

Priming tasks are used for investigating the deficits of selective attention in schizophrenia, which are thought to be related to the psychotic symptoms. Priming was assessed in acutely psychotic unmedicated (n = 22) and medicated (n = 36) schizophrenia patients and in control subjects (n = 42). The subjects had to indicate the location of a target stimulus in two consecutive stimulus displays (prime and probe). Each stimulus appeared together with a distractor on a screen. Negative Priming is characterized by an increase in reaction time, whenever a probe target is presented at a prime distractor location. Positive Priming is characterized by a decrease in reaction time, when the probe target is presented at the prime target location. Schizophrenia patients altogether showed no abnormalities in priming effects, neither in the acute phase of illness (medicated and unmedicated) nor in partial remission (one month later, medicated). In unmedicated patients however Negative Priming was inversely correlated with the severity of positive symptoms. This indicates a priming deficit in a small subgroup of severely ill patients. The data support the notion that automatic (implicit) mechanisms of learning are unimpaired in schizophrenia patients unless symptoms exceed a certain critical level.     

Sleep-related cognitive function and the K-complex in schizophrenia

Sleep parameters have been reported to be related to cognitive function in a variety of ways. Problem solving and procedural learning were found to be improved after sleep but training also affected subsequent sleep and some parameters were related to cognitive trait variables, e.g. IQ. Additional to rapid-eye-movement (REM) and slow wave sleep (SWS), micro-architectural features such as spindle activity and K-complexes have recently been the focus of interest. The study aimed at investigating the relationship of neuropsychological variables, problem solving and procedural learning with sleep parameters in stably medicated schizophrenia patients. Twenty schizophrenia out-patients participated in the study. Learning and testing occurred over a randomly balanced waking and sleep interval. The tasks were the Tower of London (ToL) and mirror tracing. Sleep EEG was analysed together with spindle activity and K-complexes. Performance improved with regard to both tasks from learning to testing irrespective of type of interval. Increasing density of K-complexes was related to a higher number of solved ToL tasks pre and post night whereas longer SWS was related to faster completion of the ToL. A higher age was related to less overnight improvement in regard to number of solved ToL tasks. K-complexes are thought to indicate intra-cortical activity paving the way for the uptake of new information. As ToL is considered a test of executive function, K-complexes appear to be linked to this domain, deficits of which are thought to be a core feature of schizophrenia.     

Fine motor performance before and after treatment in schizophrenic and schizoaffective patients

Twenty-three hospitalized patients with schizophrenia or schizoaffective disorder were tested for fine motor performance by the Crawford Small Parts Dexterity Test (CSP) and a measure of finger tapping (FT) after a 1-week medication-free period. In an attempt to evaluate potential impairment of fine motor performance, these patients were retested after 1 month's treatment with antipsychotic medication. Thirty-eight control subjects were tested and retested after 1 month by the same procedures. On medication, patients showed no decrement of performance on either test. A small practice effect was observed in both patients and control subjects between initial and second testing. Unmedicated patients had significantly lower CSP and FT scores than control subjects. On repeated testing, medicated patients also had significantly lower scores than control subjects. In the patient group, CSP and FT scores during medication were not related to dosage of medication, use of antiparkinsonian agents, or ratings of motor side effects. CSP and FT scores were significantly and inversely correlated with Brief Psychiatric Rating Scale (BPRS) subscale ratings of withdrawal- retardation (R-subscale). FT performance was positively correlated with the schizophrenia (S-subscale) of the BPRS. Global improvement, as measured by change in BPRS total score, was significantly related to improvement in CSP scores. Impairment in fine motor performance after 1 month's treatment with antipsychotic agents could not be documented. The impairment in fine motor performance in drug-free patients may be in part related to deficits of attention and cooperation. However, other deficits in motor performance have been reported in schizophrenic patients. Failure to identify fine motor impairment produced by psychotropic drugs may be related to competing effects of improved attention and motor impairment of extrapyramidal effects.     

Emotion processing and its relationship to social functioning in schizophrenia patients

Schizophrenia patients have demonstrated deficits in affect recognition. Whether this deficit is part of a general difficulty in face perception or a specific problem in affect recognition is debatable. However, there is little research investigating the functional consequences of difficulties in identifying emotion in schizophrenia patients. We tested 20 chronic, medicated schizophrenia patients and 27 normal control participants on a battery of face recognition and affect recognition tasks. A subset of 14 patients was rated on the Social Dysfunction Index. Results demonstrated that schizophrenia patients were less accurate than normal control participants on face recognition, facial affect recognition and vocal affect recognition tasks, but among schizophrenia patients, only affect recognition performance was related to social functioning. These results suggest that schizophrenia patients have general face processing deficits, but affect recognition deficits may lead to more problems in social behavior.     

State-dependent implicit learning deficit in schizophrenia: evidence from 20-month follow-up

Previous research has confirmed stable explicit memory deficits in schizophrenia across disease states. However, little is known about the implicit learning capabilities of individuals with schizophrenia across the course of illness. The current study assessed procedural learning in 19 schizophrenia subjects (DSM-IV criteria) and 19 matched controls using the Serial Reaction-Time Task (SRTT). The severity of negative, positive and disorganized symptoms was assessed using the Scales for the Assessment of Positive and Negative Symptoms. A sub-sample of 11 schizophrenia subjects and 11 controls was reassessed 20 months later when symptoms in the schizophrenia subjects had largely remitted. Schizophrenia subjects were severely impaired on sequence-specific procedural learning during an acute episode. This deficit could not be explained by a general memory or processing speed impairment. Impaired implicit learning scores were significantly related to higher ratings of disorganized symptoms. However, 20 months later, when acute symptoms had remitted, the performance of the schizophrenia subjects on procedural learning had normalized. Our findings might share a conceptual overlap with previous reports of a reduced ability of schizophrenia subjects during an acute episode to adapt ongoing perceptual and behavioral programs to previously experienced regularities in their environment.     

Motor cortical excitability in schizophrenia.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a method to examine cortico-cortical motor excitability and hemispheric asymmetry in unmedicated and medicated schizophrenia patients. METHODS: Fourteen right-handed schizophrenia patients (seven on conventional neuroleptics and seven medication-free) were compared with seven right-handed, age- and gender-matched normal control subjects. Motor threshold for induction of motor-evoked potentials (MEPs) and bihemispheric intracortical inhibition and facilitation were measured with single-pulse and paired-pulse TMS. RESULTS: Medicated patients showed an approximately 5% higher motor thresholds in both hemispheres than unmedicated patients and control subjects. Normal control subjects had a nearly 10% higher threshold for the left than the right hemisphere, whereas the opposite was true for the patient groups (5-10% higher threshold on the right than the left). Medicated patients showed significantly decreased intracortical inhibition relative to unmedicated patients and control subjects. This difference was more pronounced for the right than for the left hemisphere. CONCLUSIONS: Treatment with conventional neuroleptics is associated with increased motor threshold and decreased intracortical inhibition, whereas unmedicated patients did not differ from normal control subjects on these measures; however, schizophrenia may be characterized by a reversed pattern of interhemispheric corticospinal excitability.     

Effects of contextual processing on visual conditional associative learning in schizophrenia.

BACKGROUND: We adapted visual conditional associative learning paradigms to assess the contextual processing deficit model of schizophrenic cognitive impairment proposed by J.D. Cohen and D. Servan-Schreiber in 1992. In this task subjects learn the associations between four sets of stimuli through the use of feedback. We administered two experimental conditional associative learning conditions: in one, the eight stimuli used to make four pairs were all different; in the other, the pairs were made from different combinations of four identical stimuli, requiring the use of contextual information to mediate correct performance. Two additional associative learning tasks were administered where subjects generated the stimulus pairings or observed the experimenter form the pairs, eliminating the need to learn from feedback. METHODS: We tested 37 patients with schizophrenia and 20 healthy control subjects in each conditional associative learning task condition. RESULTS: Patients demonstrated significant impairments on all four conditional associative learning tasks. The demand to process contextual information did not differentially impact patient performance. Patients were better able to learn associations if they generated or observed the pairings rather than utilized feedback to guide learning. CONCLUSIONS: Patients with schizophrenia demonstrate pronounced deficits in the ability to utilize feedback to guide learning. We found no evidence of an additional deficit in processing of contextual information.     

Sleep restores daytime deficits in procedural memory in children with attention-deficit/hyperactivity disorder

Sleep supports the consolidation of declarative and procedural memory. While prefrontal cortex (PFC) activity supports the consolidation of declarative memory during sleep, opposite effects of PFC activity are reported with respect to the consolidation of procedural memory during sleep. Patients with attention-deficit/hyperactivity disorder (ADHD) are characterised by a prefrontal hypoactivity. Therefore, we hypothesised that children with ADHD benefit from sleep with respect to procedural memory more than healthy children. Sixteen children with ADHD and 16 healthy controls (aged 9-12) participated in this study. A modification of the serial-reaction-time task was conducted. In the sleep condition, learning took place in the evening and retrieval after a night of sleep, whereas in the wake condition learning took place in the morning and retrieval in the evening without sleep. Children with ADHD showed an improvement in motor skills after sleep compared to the wake condition. Sleep-associated gain in reaction times was positively correlated with the amount of sleep stage 4 and REM-density in ADHD. As expected, sleep did not benefit motor performance in the group of healthy children. These data suggest that sleep in ADHD normalizes deficits in procedural memory observed during daytime. It is discussed whether in patients with ADHD attenuated prefrontal control enables sleep-dependent gains in motor skills by reducing the competitive interference between explicit and implicit components within a motor task.     

Procedural memory in Parkinson's disease: impaired motor but not visuoperceptual learning

A current model proposes that memory consists of two functionally separate systems that have different neurological substrates. Declarative memory appears to be dependent on the diencephalic medial temporal lobe system whereas some speculate that the basal ganglia may be a neurological substrate for procedural memory. This study tested the role of the basal ganglia in regulating different types of procedural skills by comparing performance on a motor and a visuoperceptual skill learning task. Twenty Parkinson's (PD) patients and 20 normal control subjects performed two procedural learning tasks (rotary pursuit and mirror reading) and one declarative learning task (paired associates) over 3 days. The results showed that PD patients were not impaired on mirror reading or paired associate learning. On rotary pursuit, performance levels on day 1 were similar between groups, but the PD group showed less improvement across days than controls. However, only patients with more advanced symptoms of PD showed impaired rotary pursuit learning, and this could not be attributed directly to deficits in primary motor or general cognitive function. These findings suggest that the underlying processes/procedures for procedural learning are specific to the task, and are supported by different neuroanatomical systems.     

TMS-assisted neurophysiological profiling of the dopamine receptor agonist cabergoline in human motor cortex

Summary. Dopamine plays a broad role in motor control and practice-dependent plasticity. Here we tested, in eight healthy subjects, the effects of the dopamine receptor agonist cabergoline on motor cortical excitability because the state of motor cortex can strongly influence practice-dependent plasticity. Cabergoline enhances practice-dependent plasticity but the mechanisms are unknown. We used transcranial magnetic stimulation for testing of motor cortical excitability. A single dose of 2 mg of cabergoline increased short-interval intracortical inhibition, a measure of excitability of GABA-dependent inhibitory neural circuits, and decreased various excitatory measures (motor evoked potential amplitude and short-interval intracortical facilitation). Other measures of motor cortical (motor threshold, cortical silent period duration), spinal (peripheral silent period duration, F-wave) and neuromuscular excitability (maximum M-wave) remained unchanged. This shift in the balance from excitation to inhibition may assist, by improving the ‘signal-to-noise ratio’ in motor cortex, in the positive modulating effect of cabergoline on practice-dependent plasticity.     

Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.