Neuroplastic changes in patients with schizophrenia undergoing cognitive remediation: triple-blind trial.
ABSTRACT: BackgroundPatients with schizophrenia have shown cognitive improvements following cognitive remediation, but the neuroplastic changes that support these processes are not fully understood.AimsTo use a triple-blind, placebo-controlled trial to examine neural activation before and after cognitive remediation or a computer skills training (CST) placebo (trial registration: NCT00995553)).MethodTwenty-seven participants underwent functional magnetic resonance imaging before and after being randomised to either cognitive remediation intervention or CST. Participants completed two variants of the N-back task during scanning and were assessed on measures of cognition, functional capacity, community functioning and symptoms.ResultsWe observed a group × time interaction in the left prefrontal cortex, wherein the cognitive remediation group showed increased activation. These changes correlated with improved task accuracy within the cognitive remediation group, whereas there was no relationship between changes in activation in untrained cognitive measures. Significant changes were not observed in other hypothesised areas for the cognitive remediation group.ConclusionsWe replicated the finding that cognitive remediation increases left lateral prefrontal activation during a working memory task in patients with schizophrenia, suggesting this may be an important neural target for these types of interventions.
Project description:BACKGROUND:Thalamic projections to the prefrontal cortex (PFC) are critical for cognition, and disruptions in these circuits are thought to underlie the pathophysiology of schizophrenia. Cognitive remediation (REM) is a behavioral intervention that holds promise for improving cognition and functioning in schizophrenia, however the extent to which it affects thalamo-prefrontal connections has not been researched. This study sought to determine whether patients with schizophrenia who undergo a placebo-controlled trial of REM show increased functional connectivity between the thalamus and PFC, and whether these changes correspond to improvements in cognition. METHODS:Twenty-six patients with chronic schizophrenia were randomized to either 48 hours (over 16 weeks) of a drill-and-practice working memory-focused REM or an active placebo condition. All participants underwent cognitive assessment (MATRICS Consensus Cognitive Battery), as well as both resting and task-based fMRI before and after their respective intervention. All clinicians, technicians, and raters were blind to participant condition. RESULTS:We observed changes in resting-state connectivity in the PFC for the REM group but not the placebo group. Increased intrinsic connectivity between the thalamus and right middle frontal gyrus correlated with improvements in overall cognition. Additionally, lower baseline cognition correlated with greater increases in connectivity between the thalamus and PFC. Similar findings were observed when patients were scanned during a working memory task. CONCLUSIONS:These results suggest that increases in thalamo-prefrontal circuitry correspond with training-related improvements of the cognitive deficits associated with schizophrenia.
Project description:Cognitive remediation training (CRT) for schizophrenia has been found to improve cognitive functioning and influence neural plasticity. However, with various training approaches and mixed findings, the mechanisms driving generalization of cognitive skills from CRT are unclear. In this meta-analysis of extant imaging studies examining CRT's effects, we sought to clarify whether varying approaches to CRT suggest common neural changes and whether such mechanisms are restorative or compensatory. We conducted a literature search to identify studies appropriate for inclusion in an activation likelihood estimation (ALE) meta-analysis. Our criteria required studies to consist of training-based interventions designed to improve patients' cognitive or social functioning, including generalization to untrained circumstances. Studies were also required to examine changes in pre- vs posttraining functional activation using functional magnetic resonance imaging or positron emission tomography. The literature search identified 162 articles, 9 of which were appropriate for inclusion. ALE analyses comparing pre- and posttraining brain activation showed increased activity in the lateral and medial prefrontal cortex (PFC), parietal cortex, insula, and the caudate and thalamus. Notably, activation associated with CRT in the left PFC and thalamus partially overlapped with previous meta-analytically identified areas associated with deficits in working memory, executive control, and facial emotion processing in schizophrenia. We conclude that CRT interventions from varying theoretic modalities elicit plasticity in areas that support cognitive and socioemotional processes in this early set of studies. While preliminary, these changes appear to be both restorative and compensatory, though thalamocortical areas previously associated with dysfunction may be common sources of plasticity for cognitive remediation in schizophrenia.
Project description:Cognitive remediation involves task practice and may improve deficits in people suffering from schizophrenia, but little is known about underlying neurophysiological mechanisms. In people with schizophrenia and controls, we used magnetoencephalography (MEG) to examine accuracy and practice-related changes in parameters indexing neural network structure and activity, to determine whether these might be useful assays of the efficacy of cognitive remediation. Two MEG recordings were acquired during performance of a tone discrimination task used to improve the acuity of auditory processing, before and after ?2.5?h of task practice. Accuracy before practice was negatively correlated with beta-band cost efficiency, a graph theoretical measure of network organization. Synthetic aperture magnetometry was used to localize brain oscillations with high spatial accuracy; results demonstrated sound and sensorimotor modulations of the beta band in temporo-parietal regions and the sensorimotor cortex respectively. High-gamma activity also correlated with sensorimotor processing during the task, with activation of auditory regions following sound stimulation, and activation of the left sensorimotor cortex preceding the button press. High-gamma power in the left frontal cortex was also found to correlate with accuracy. Following practice, sound-induced broad-band power in the left angular gyri increased. Accuracy improved and was found to correlate with increased mutual information (MI) between sensors in temporal-parietal regions in the beta band but not global cost efficiency. Based on these results, we conclude that hours of task practice can induce meso-scale changes such as increased power in relevant brain regions as well as changes in MI that correlate with improved accuracy.
Project description:OBJECTIVE:Cognitive remediation is emerging as an effective psychosocial intervention for addressing untreated cognitive and functional impairments in persons with schizophrenia, and might achieve its benefits through neuroplastic changes in brain connectivity. This study seeks to examine the effects of cognitive enhancement therapy (CET) on fronto-temporal brain connectivity in a randomized controlled trial with individuals in the early course of schizophrenia. METHOD:Stabilized, early course outpatients with schizophrenia or schizoaffective disorder (N = 41) were randomly assigned to CET (n = 25) or an active enriched supportive therapy (EST) control (n = 16) and treated for 2 years. Functional MRI data were collected annually, and pseudo resting-state functional connectivity analysis was used to examine differential changes in fronto-temporal connectivity between those treated with CET compared with EST. RESULTS:Individuals receiving CET evidenced significantly less functional connectivity loss between the resting-state network and the left dorsolateral prefrontal cortex as well as significantly increased connectivity with the right insular cortex compared to EST (all corrected p < .01). These neural networks are involved in emotion processing and problem-solving. Increased connectivity with the right insula significantly mediated CET effects on improved emotion perception (z' = -1.96, p = .021), and increased connectivity with the left dorsolateral prefrontal cortex mediated CET-related improvements in emotion regulation (z' = -1.71, p = .052). CONCLUSIONS:These findings provide preliminary evidence that CET, a psychosocial cognitive remediation intervention, may enhance connectivity between frontal and temporal brain regions implicated in problem-solving and emotion processing in service of cognitive enhancement in schizophrenia.
Project description:LPFC dysfunction is a well-established neural impairment in schizophrenia and is associated with worse symptoms. However, how LPFC activation influences symptoms is unclear. Previous findings in healthy individuals demonstrate that lateral prefrontal cortex (LPFC) activation during cognitive control of emotional information predicts mood and behavior in response to interpersonal conflict, thus impairments in these processes may contribute to symptom exacerbation in schizophrenia. We investigated whether schizophrenia participants show LPFC deficits during cognitive control of emotional information, and whether these LPFC deficits prospectively predict changes in mood and symptoms following real-world interpersonal conflict. During fMRI, 23 individuals with schizophrenia or schizoaffective disorder and 24 healthy controls completed the Multi-Source Interference Task superimposed on neutral and negative pictures. Afterwards, schizophrenia participants completed a 21-day online daily-diary in which they rated the extent to which they experienced mood and schizophrenia-spectrum symptoms, as well as the occurrence and response to interpersonal conflict. Schizophrenia participants had lower dorsal LPFC activity (BA9) during cognitive control of task-irrelevant negative emotional information. Within schizophrenia participants, DLPFC activity during cognitive control of emotional information predicted changes in positive and negative mood on days following highly distressing interpersonal conflicts. Results have implications for understanding the specific role of LPFC in response to social stress in schizophrenia, and suggest that treatments targeting LPFC-mediated cognitive control of emotion could promote adaptive response to social stress in schizophrenia.
Project description:The goal of this study was to use transcranial direct current stimulation (tDCS) to examine the role of the prefrontal cortex (PFC) in neural oscillatory activity associated with proactive cognitive control in schizophrenia. To do so, we tested the impact of PFC-targeted tDCS on behavioral and electrophysiological markers of proactive cognitive control engagement in individuals with schizophrenia. Using a within-participants, double-blinded, sham-controlled crossover design, we recorded EEG while participants with schizophrenia completed a proactive cognitive control task (the Dot Pattern Expectancy (DPX) Task), after receiving 20?min of active prefrontal stimulation at 2?mA or sham stimulation. We hypothesized that active stimulation would enhance proactive cognitive control, leading to changes in behavioral performance on the DPX task and in activity in the gamma frequency band during key periods of the task designed to tax proactive cognitive control. The results showed significant changes in the pattern of error rates and increases in EEG gamma power as a function of tDCS condition (active or sham), that were indicative of enhanced proactive cognitive control. These findings, considered alongside our previous work in healthy adults, provides novel support for the role gamma oscillations in proactive cognitive control and they suggest that frontal tDCS may be a promising approach to enhance proactive cognitive control in schizophrenia.
Project description:This study aimed to test how an 8-week training using computerized cognitive remediation therapy (CCRT) would modify resting brain functional activity and improve cognitive function in patients with schizophrenia. Twenty-seven patients with schizophrenia were recruited and randomized into two groups: CCRT or treatment-as-usual (TAU). The CCRT group received 40 sessions of computerized cognitive training over an eight-week period. There was a significant treatment group × time interaction on the processing speed (trail making test: F?=?8.14, P?=?0.01) and a trend in problem solving (mazes test: P?=?0.06). Post-hoc tests showed that CCRT but not TAU significantly improved scores from baseline to end-of-treatment on these two cognitive assessments. For the resting brain functional activity, significant group × time interaction effect was found in the medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC) and brainstem pons region. Post-hoc tests showed that there was significant increased activity in the mPFC/ACC in CCRT but not TAU group. In this small sample study, computerized cognitive remediation therapy is shown to enhance mPFC/ACC activity even at resting state and improve cognitive function in patients with schizophrenia. If replicated, this community and clinic accessible therapy may assist cognitive remediation effort for people with schizophrenia.
Project description:This is a data article from the original publication "Effect of aerobic exercise combined with cognitive remediation on cortical thickness and prediction of social adaptation in patients with schizophrenia" . Twenty-one patients with schizophrenia and 23 healthy controls underwent aerobic exercise. Another 21 patients with schizophrenia played table soccer instead. The 12-week exercise intervention was combined with computer-assisted cognitive remediation training from week 6 to week 12. Clinical assessments were conducted at baseline and after the 12-week intervention. Magnetic resonance imaging (MRI) scans were acquired at baseline then in weeks 6, 12, and 24. The thickness of the entorhinal, parahippocampal, and lateral and medial prefrontal cortices was assessed with FreeSurfer 6.0. Data are publicy available via https://osf.io/sfgxk/.
Project description:Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases.Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load.Task accuracy was similar in patients and healthy participants. However, patients showed reductions in brain activation during maintenance and response phases but not during the encoding phase. The reduced prefrontal activity during the maintenance phase of working memory was attributed to a greater rate of decay of prefrontal activity over time in patients. Cortical deficits in patients did not appear to be related to antipsychotic treatment. In patients and in healthy subjects, the time-dependent reduction in prefrontal activity during working memory maintenance correlated with poorer performance on the memory task.Overall, these data highlight that basic research insights into the distinct neurobiologies of the maintenance and response phases of working memory are of potential importance for understanding the neurobiology of cognitive impairment in schizophrenia and advancing its treatment.
Project description:Both cognitive and social-cognitive deficits impact functional outcome in schizophrenia. Cognitive remediation studies indicate that targeted cognitive and/or social-cognitive training improves behavioral performance on trained skills. However, the neural effects of training in schizophrenia and their relation to behavioral gains are largely unknown. This study tested whether a 50-h intervention which included both cognitive and social-cognitive training would influence neural mechanisms that support social ccognition. Schizophrenia participants completed a computer-based intervention of either auditory-based cognitive training (AT) plus social-cognition training (SCT) (N=11) or non-specific computer games (CG) (N=11). Assessments included a functional magnetic resonance imaging (fMRI) task of facial emotion recognition, and behavioral measures of cognition, social cognition, and functional outcome. The fMRI results showed the predicted group-by-time interaction. Results were strongest for emotion recognition of happy, surprise and fear: relative to CG participants, AT+SCT participants showed a neural activity increase in bilateral amygdala, right putamen and right medial prefrontal cortex. Across all participants, pre-to-post intervention neural activity increase in these regions predicted behavioral improvement on an independent emotion perception measure (MSCEIT: Perceiving Emotions). Among AT+SCT participants alone, neural activity increase in right amygdala predicted behavioral improvement in emotion perception. The findings indicate that combined cognition and social-cognition training improves neural systems that support social-cognition skills.