Reduced transfer of visuomotor adaptation is associated with aberrant sense of agency in schizophrenia.

One deficit associated with schizophrenia (SZ) is the reduced ability to distinguish self-caused sensations from those due to external sources. This reduced sense of agency (SoA, subjective awareness of control over one's actions) is hypothesized to result from a diminished utilization of internal monitoring signals of self-movement (i.e., efference copy) which subsequently impairs forming and utilizing sensory prediction errors (differences between the predicted and actual sensory consequences resulting from movement). Another important function of these internal monitoring signals is the facilitation of higher-order mechanisms related to motor learning and control. Current predictive-coding models of adaptation postulate that the sensory consequences of motor commands are predicted based on internal action-related information, and that ownership and control of motor behavior is modified in various contexts based on predictive processing. Here, we investigated the connections between SoA and motor adaptation. Schizophrenia patients (SZP, N=30) and non-psychiatric control subjects (HC, N=31) adapted to altered movement visual feedback and applied the motor recalibration to untested contexts (i.e., the spatial generalization). Although adaptation was similar for SZP and controls, the extent of generalization was significantly less for SZP; movement trajectories made by patients to the furthest untrained target (135o) before and after adaptation were largely indistinguishable. Interestingly, deficits in generalization were correlated with positive symptoms of psychosis in SZP (e.g., hallucinations). Generalization was also associated with measures of SoA across both SZP and HC, emphasizing the role action awareness plays in motor behavior, and suggesting that misattributing agency, even in HC, manifests in abnormal motor performance.

Social rehabilitation for military veterans with traumatic brain injury, psychological trauma, and chronic neuropsychiatric symptoms: Intervention development and initial outcomes.

OBJECTIVE: A subset of military veterans who have experienced both traumatic brain injury and psychological trauma present with chronic neuropsychiatric symptoms and experience persistent obstacles to social reintegration. This project aimed to develop a novel treatment targeting the unmet social rehabilitation needs of these veterans. Initial intervention development, feasibility, and outcome data are explored. METHOD: Four treatment groups were conducted (n = 20). A treatment workbook was developed during Groups 1 and 2 (n = 10) and research data were collected from Groups 3 and 4 (n = 10). RESULTS: There was a 0% attrition rate across all groups with unanimous requests for additional sessions. T test effect sizes were analyzed with bias-corrected Hedges' g. Improvements were observed on measures of depression (p = .026, g = 0.73), empathic perspective taking (p = .007, g = 0.94), social cognition (p = .002-.678, g = 0.27-1.30 across multiple measures), social relationships (p = .007, g = 1.50), traumatic brain injury-related quality of life (social: p = .014, g = 0.68, emotional: p = .009, g = 1.28) and nonsocial executive functioning (p = .006, g = 0.54). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Preliminary evidence from this exploratory study suggests that targeting multiple layers of social competence using a combined psychotherapy and cognitive rehabilitation approach holds promise. Larger, controlled studies are needed to further evaluate the feasibility and efficacy of this intervention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Transsaccadic Perception Deficits in Schizophrenia Reflect the Improper Internal Monitoring of Eye Movement Rather Than Abnormal Sensory Processing.

BACKGROUND: Symptoms of psychosis in schizophrenia reflect disturbances in sense of agency-difficulty distinguishing internally from externally generated sensory and perceptual experiences. One theory attributes these anomalies to a disruption in corollary discharge (CD), an internal copy of generated motor commands used to distinguish self-movement-generated sensations from externally generated stimulation. METHODS: We used a transsaccadic shift detection paradigm to examine possible deficits in CD and sense of agency based on the ability to perceive visual changes in 31 schizophrenia patients (SZPs) and 31 healthy control subjects. We derived perceptual measures based on manual responses indicating the transsaccadic target shift direction. We also developed a distance-from-unity-line measure to quantify use of CD versus purely sensory (visual) information in evaluating visual changes in the environment after an eye movement. RESULTS: SZPs had higher perceptual thresholds in detecting shift of target location than healthy control subjects, regardless of movement direction or amplitude. Despite producing similar hypometric saccades, healthy control subjects overestimated target location, whereas SZPs relied more on the experienced visual error and consequently underestimated the target position. We show that in SZPs the postsaccadic judgment of the initial target location was largely aligned with the measure based only on visual error, suggesting a deficit in the use of CD. This CD deficit also correlated with positive schizophrenia symptoms and disturbances in sense of agency. CONCLUSIONS: These results provide a novel approach in quantifying abnormal use of CD in SZPs and provide a framework to distinguish deficits in sensory processing versus defects in the internal CD-based monitoring of movement.

Neuropsychological measurement of inhibitory control in posttraumatic stress disorder: An exploratory antisaccade paradigm.

OBJECTIVE: The aim of the study was to uncover inhibitory control dynamics and assess antisaccade eye-tracking tasks for relevance in a veteran posttraumatic stress disorder (PTSD) population. METHOD: Participants were 36 veterans enrolled at the Washington DC Veterans Affairs Medical Center. The groups (PTSD diagnosed vs. controls) did not vary between age and sex. Participants completed a testing battery of clinical neuropsychological measures and two different eye-tracking conditions, one that utilized face stimuli and one with standard shape stimuli, which test pro- (PS) and antisaccade (AS) eye movements. RESULTS: Veterans with PTSD, t(33) = 2.2, p = .04, took longer to respond than controls in the standard condition AS. In the face condition, a group by task interaction was seen with increased latency for PTSD veterans in the AS versus PS task, F(3, 33) = 3.99, p = .05, with a large overall effect (Hedges' g = 1.18, p < .001) compared to controls. After controlling for depression, analyses suggested that only the face condition AS task significantly predicted dimensions of PTSD symptomology measured by the Clinician Administered PTSD Scale (CAPS) for veterans with PTSD. CONCLUSIONS: This is the first study to extend AS findings to PTSD and suggests a specific capability to measure inhibitory control using eye-tracking technology. We discuss the notion that reduced capacity to regulate facial-related processing affects cognitive and attentional control networks of PTSD patients, potentially representing a core cognitive deficit.

Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy.

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state. We conducted a single-site, double-blind randomized clinical trial comparing galantamine/CDP-choline to placebos in schizophrenia patients with negative symptoms who were receiving second generation antipsychotics. Forty-three subjects received galantamine and CDP-choline or matching placebos for 16weeks. The primary outcome measure was the 5-item Marder negative-symptoms factor of the Positive and Negative Syndrome Scale (PANSS). Cognition and functioning were also assessed. Trial completion was high; 79%. There was no significant treatment effect on negative symptoms, other PANSS symptom factors, or the MATRICS Cognitive Consensus Battery. There were significant treatment effects in overall functioning and a test of free verbal recall. Three subjects discontinued treatment in the active treatment group for gastro-intestinal adverse events (AE). The most common AE for galantamine/CDP-choline was abdominal pain; for placebo it was headache and sweating. Although there was no significant treatment effect on negative symptoms, the direction of effect mirrored the effects on a cognitive measure and overall functioning. Further study of α7 nAChR agonist/PAMs is warranted in larger studies that will have greater power.

Neural basis of implicit memory for socio-emotional information in schizophrenia.

Individuals with schizophrenia are impaired in processing social signals such as facial expressions of emotion. Perceiving facial expressions is a complex process that depends on a distributed neural network of regions involved in affective, cognitive, and visual processing. We examined repetition priming, a non-conscious form of perceptual learning, to explore the visual-perceptual processes associated with perceiving facial expression in people with schizophrenia. Functional magnetic resonance imaging (fMRI) was also employed to probe the sensitivity of face-responsive regions in the ventral pathway to the repetition of stimuli. Subjects viewed blocks of novel and repeated faces displaying fear expressions and neutral expressions and identified each face as male or female. Gender decisions were faster for repeated encoding relative to initial encoding of faces, indicating significant priming for facial expressions. Priming was normal in schizophrenia patients, but, as expected, recognition memory for the expressions was impaired. Neuroimaging findings showed that priming-related activation for patients was reduced in the left fusiform gyrus, relative to controls, regardless of facial expression. The findings suggest that schizophrenia patients have altered neural sensitivity in regions of the ventral visual processing stream that underlie early perceptual learning of objects and faces.

Attention to gaze and emotion in schizophrenia.

OBJECTIVE: Individuals with schizophrenia have difficulty interpreting social and emotional cues such as facial expression, gaze direction, body position, and voice intonation. Nonverbal cues are powerful social signals but are often processed implicitly, outside the focus of attention. The aim of this research was to assess implicit processing of social cues in individuals with schizophrenia. METHOD: Patients with schizophrenia or schizoaffective disorder and matched controls performed a primary task of word classification with social cues in the background. Participants were asked to classify target words (LEFT/RIGHT) by pressing a key that corresponded to the word, in the context of facial expressions with eye gaze averted to the left or right. RESULTS: Although facial expression and gaze direction were irrelevant to the task, these facial cues influenced word classification performance. Participants were slower to classify target words (e.g., LEFT) that were incongruent to gaze direction (e.g., eyes averted to the right) compared to target words (e.g., LEFT) that were congruent to gaze direction (e.g., eyes averted to the left), but this only occurred for expressions of fear. This pattern did not differ for patients and controls. CONCLUSION: The results showed that threat-related signals capture the attention of individuals with schizophrenia. These data suggest that implicit processing of eye gaze and fearful expressions is intact in schizophrenia.

Regulation of intermittent oscillatory activity of pyramidal cell neurons by GABA inhibitory interneurons is impaired in schizophrenia: rationale for pharmacotherapeutic GABAergic interventions.

GABA, the major inhibitory neurotransmitter in the brain, is synthesized from L-glutamate and packaged within a family of highly differentiated inhibitory interneurons. Individual GABA inhibitory interneurons in the frontal cortex can make terminal synaptic connections with more than 200 distinct pyramidal neurons, the principal output neuron. Moreover, the sites of these synaptic connections include shafts of dendritic spines, soma, dendritic branches, and initial axon segments. The phasic activity of GABAergic neurons regulate intermittent oscillations of assemblies of pyramidal cell neurons, which are critical for many higher cortical functions such as working memory. Potentially, there are several viable pharmacotherapeutic strategies for facilitating GABAergic neurotransmission. A major research question is whether tonically-administered, selective GABAergic therapeutic interventions can mimic and correct disruptions of the intermittent oscillatory activity of assemblies of cortical pyramidal cell neurons.

Recognition memory probes affect what is remembered in schizophrenia.

Cognitive psychology offers tools to localize the memory processes most vulnerable to disruption in schizophrenia and to identify how patients with schizophrenia best remember. In this research, we used the University of Southern California Repeatable Episodic Memory Test (USC-REMT; Parker, E.S., Landau, S.M., Whipple, S.C., Schwartz, B.L., 2004. Aging, recall, and recognition: A study on the sensitivity of the University of Southern California Repeatable Episodic Memory Test (USC-REMT). Journal of Clinical and Experimental Neuropsychology 26(3), 428-440.) to examine how two different recognition memory probes affect memory performance in patients with schizophrenia and matched controls. Patients with schizophrenia studied equivalent word lists and were tested by yes-no recognition and forced-choice recognition following identical encoding and storage conditions. Compared with controls, patients with schizophrenia were particularly impaired when tested by yes-no recognition relative to forced-choice recognition. Patients had greatest deficits on hits in yes-no recognition but did not exhibit elevated false alarms. The data point to the importance of retrieval processes in schizophrenia, and highlight the need for further research on ways to help patients with schizophrenia access what they have learned.

First administration of cytidine diphosphocholine and galantamine in schizophrenia: a sustained alpha7 nicotinic agonist strategy.

Converging lines of evidence suggest pathophysiology of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) in schizophrenia. This pilot study was designed to test the tolerability, safety, and preliminary efficacy of chronic administration of an alpha7 nAChR agonist strategy involving combination treatment of cytidine diphosphocholine (CDP-choline; 2 g/d), a dietary source of the alpha7 nAChR agonist choline, and galantamine (24 mg/d), a positive allosteric modulator of nAChRs that was prescribed to prevent choline from becoming a functional antagonist and improve the efficiency of coupling the binding of choline to channel opening. The combination of CDP-choline and galantamine was administered to 6 schizophrenic patients with residual symptoms in a 12-week, open-label trial. Patients were maintained on stable dose regimens of antipsychotic medications for 4 weeks before study entry and for the trial duration. All reached target doses of both agents and completed the trial. Transient side effects resolved without slowing of dose titration. Gastrointestinal adverse effects were most common. Of the 6 patients, 5 showed reduction in Clinical Global Impressions severity scores and Positive and Negative Syndrome Scale total scores. Three patients requested continuation of the adjunctive combination at the end of the trial. These results suggest further investigation of the combination of CDP-choline and galantamine as an alpha7 nAChR agonist intervention.

Effects of CDP-choline and the combination of CDP-choline and galantamine differ in an animal model of schizophrenia: development of a selective alpha7 nicotinic acetylcholine receptor agonist strategy.

The regionally selective reduction of expression of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in schizophrenia underlies impaired sensory inhibition, a possible endophenotype of the disorder. This ligand-gated ion channel receptor has been proposed as a pharmacotherapeutic target in schizophrenia. The current study examined the effect of CDP-choline alone and the combination of CDP-choline and galantamine, administered acutely and once-daily for five consecutive days, in an animal model of NMDA receptor hypofunction that is relevant to schizophrenia. The results support the allosteric modulatory influence of galantamine on CDP-choline; however, individual doses of CDP-choline and galantamine must be carefully titrated in order to achieve optimal levels of alpha7 nAChR "agonism" that may be necessary for the desired therapeutic effect.

Williams syndrome: a genetic deletion disorder presenting clues to the biology of sociability and clinical challenges of hypersociability.

Williams syndrome is a neurodevelopmental disorder that results from the deletion of approximately 25-30 genes spanning about 1.5 megabases in the q11.23 region of chromosome 7. Patients with this syndrome present with a combination of a distinctive elfin-like facial appearance; growth retardation; mild mental retardation; an inconsistent cognitive profile that includes visuospatial impairments with good facial discrimination and relatively preserved expressive language skills; and cardiovascular abnormalities. In addition, a striking behavioral feature of the syndrome is the high sociability and empathy that these patients show for others. The study of patients with "partial" deletions of the chromosome band 7q11.23, mutated genes in this region and knockout mice with deletions of specific genes in the homologous G1-G2 region of mouse chromosome 5 are clarifying some genotype/phenotype relationships. Furthermore, genes located in this region that are prominently expressed have been implicated in brain development and function. The neuropsychological profile of patients with Williams syndrome is heterogeneous, highlights important dissociations between cognitive functions and suggests that the behavioral dimensions of sociability, empathy, engageability, and talkativeness may be independent of, or not easily explained by, the cognitive deficits. Williams syndrome has enormous heuristic value because its pathological feature of heightened "sociability" can be a "deficit" symptom of major complex neuropsychiatric disorders, such as schizophrenia and autism. Data consistent with a core inability of patients with Williams syndrome to inhibit social approach suggest that this disorder may afford an opportunity to study the biological basis of the "drive" toward socialization. From a research perspective, the syndrome lends itself to neurobiological studies of sociability as a dimension that varies independently of cognition (or at least many separable cognitive processes). Importantly, from a clinical perspective, the syndrome challenges us to administer strategic psychosocial interventions that take advantage of the opportunities that "pathological" sociability provide, while avoiding its threats. An illustrative example of an effective strategically planned psychosocial intervention for a patient with Williams syndrome is briefly presented.

Imitation of facial expressions in schizophrenia.

Diminished facial expressivity is a common feature of schizophrenia that interferes with effective interpersonal communication. This study was designed to determine if real-time visual feedback improved the ability of patients with schizophrenia to imitate and produce modeled facial expressions. Twenty patients with schizophrenia and 10 controls viewed static images of facial expressions and were asked to imitate them. Half of the images were imitated with the use of a mirror and half were imitated without the use of a mirror. In addition, we examined whether practice in imitating and producing expressions improved the ability of participants to generate facial expressions on their own, without the aid of a model or mirror. Participants' facial expressions were photographed with a digital camera and each was rated for accuracy in producing characteristic facial expressions. Patients with schizophrenia were less accurate in imitating and producing facial expressions than controls, and real-time visual feedback did not improve accuracy in either group. Preliminary findings suggest that exposure to model expressions and practice in generating these expressions can improve the accuracy of certain posed expressions in schizophrenia.

Implicit learning of non-spatial sequences in schizophrenia.

Recent studies have reported abnormal implicit learning of sequential patterns in patients with schizophrenia. Because these studies were based on visuospatial cues, the question remained whether patients were impaired simply due to the demands of spatial processing. This study examined implicit sequence learning in 24 patients with schizophrenia and 24 healthy controls using a non-spatial variation of the serial reaction time test (SRT) in which pattern stimuli alternated with random stimuli on every other trial. Both groups showed learning by responding faster and more accurately to pattern trials than to random trials. Patients, however, showed a smaller magnitude of sequence learning. Both groups were unable to demonstrate explicit knowledge of the nature of the pattern, confirming that learning occurred without awareness. Clinical variables were not correlated with the patients' learning deficits. Patients with schizophrenia have a decreased ability to develop sensitivity to regularly occurring sequences of events within their environment. This type of deficit may affect an array of cognitive and motor functions that rely on the perception of event regularity.

Therapeutic implications of a selective alpha7 nicotinic receptor abnormality in schizophrenia.

A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of reduced expression and function of the alpha7 nicotinic receptor in patients with schizophrenia. The alpha7 nicotinic receptor is a member of a family of ligand-gated ion channels. The alpha7 nicotinic receptor may play an essential role in auditory sensory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in patients with schizophrenia and closely related unaffected biological relatives. Diminished expression or function of the alpha7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial alpha7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modulators of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine).

Memory encoding and retrieval on the ascending and descending limbs of the blood alcohol concentration curve.

RATIONALE: Little is known about acute effects of alcohol on memory encoding and retrieval on different limbs (ascending and descending) of the blood alcohol concentration (BAC) curve. OBJECTIVES: This extensive experiment was designed to examine alcohol's effects on memory encoding and retrieval throughout a protracted drinking episode. METHODS: In a 9-h session, male participants consumed either alcohol (1 ml/kg) or placebo (n = 32/32) over a period of 90 min and learned various materials in different memory tasks before, during, and after consuming the drinks, while their BAC levels were monitored. A week later, in a similar session, they were tested on learned materials before, during, and after drinking. Mood was assessed throughout both sessions. RESULTS: Alcohol impaired recall of words more than recognition, and cued recall most severely. Perceptual priming and picture recognition were not affected by alcohol. Alcohol impaired encoding in cued recall, recognition of completed word fragments, and free recall regardless of limb, but impaired retrieval in word recognition only during the ascending BAC. Alcohol increased negative mood on the descending limb during the first session, and on the ascending limb during the second session. CONCLUSIONS: Under naturalistic drinking conditions, alcohol's effects on memory depend on task, memory process, and limb of the BAC curve. The differential effects of alcohol on retrieval during the ascending and descending limbs demonstrate the importance of examining the differential effects on the two limbs.

Aging, recall and recognition: a study on the sensitivity of the University of Southern California Repeatable Episodic Memory Test (USC-REMT).

This study examines the sensitivity of the University of Southern California Repeatable Episodic Memory Test (USC-REMT) to the effects of aging in a sample of 112 men and women from 18 to 93 years old. Two new recognition measures, yes-no and forced-choice, were developed to supplement the original USC-REMT which measured only free-recall. Free-recall, yes-no recognition and forced-choice recognition were sensitive to age effects, with free-recall being the most sensitive. The seven recall and recognition lists can be used interchangeably. The data indicate that the USC-REMT is worthy of consideration when there is a need for a brief, screening tool of various memory functions, particularly when there is interest in memory changes over time and repeated assessments.

A quantitative measure of postural sway deficits in schizophrenia.

Clinicians rely on observational methods to assess obvious signs of postural abnormalities in schizophrenia, yet subtle signs of postural deficits may go unnoticed. Posture is controlled, in large part, by the cerebellum, which has been implicated in numerous reports of structural and functional deficits in schizophrenia. Given the possibility of an underlying disruption of cerebellar function in schizophrenia, this study used an objective, quantitative measure to assess the magnitude of postural stability in this disorder. A total of 36 schizophrenia patients and 36 non-psychiatric age-matched controls stood on a pressure-sensitive platform that recorded shifts in weight (body sway) through pressure points in the feet. Patients demonstrated more postural sway than did healthy controls (p<0.01). When patients with noticeable signs of tardive dyskinesia were removed from analyses, group differences remained (p<0.01). There was no significant correlation between neuroleptic medication level and degree of postural sway (r=0.16, p=0.37). These results indicate that patients with schizophrenia have subtle, yet quantifiable, disturbances in the control of posture and balance. Quantitative measures of postural sway may provide a more sensitive means of detecting disturbances of movement than do standard clinical observations alone.

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.

Implicit learning of visuospatial sequences in schizophrenia.

The authors examined whether patients with schizophrenia learned sequential patterns in a probabilistic serial response time task in which pattern trials alternated with random ones. Patients showed faster and more accurate responses to pattern trials than to random trials, but controls showed greater sensitivity to patterns. The highest level of regularity learned in both groups was information about runs of 3 events. Pattern learning occurred largely outside of awareness, as participants could not describe patterns. Controls with higher memory spans learned the sequential pattern better than those with lower memory spans, suggesting that working memory influences implicit pattern learning. Pathology in motor sequencing systems and poor working memory may lead to deficits in learning sequence structure in schizophrenia.