Stimulating learning: A functional MRI and behavioral investigation of the effects of transcranial direct current stimulation on stochastic learning in schizophrenia.

Transcranial direct current stimulation (tDCS) of the medial prefrontal cortex (mPFC) is under clinical investigation as a treatment for cognitive deficits. We investigate the effects of tDCS over the mPFC on performance SSLT in individuals with schizophrenia, and the underlying neurophysiological effect in regions associated with learning values and stimulus-outcome relationships. In this parallel-design double-blind pilot study, 49 individuals with schizophrenia, of whom 28 completed a fMRI, were randomized into active or sham tDCS stimulation groups. Subjects participated in 4 days of SSLT training (days 1, 2, 14, 56) with tDCS applied at day-1, and during a concurrent MRI scan at day-14. The SSLT demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 and at day-56. Active tDCS was associated with increased insular activity, and reduced amygdala activation. tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia, with this study being the first to show a longer-term effect on SSLT.

The effect of training intensity on implicit learning rates in schizophrenia.

Cognitive impairments in learning and memory are core symptoms of schizophrenia, associated with reduced self-reported quality of life. The most effective treatment of cognitive impairments is drill and practice cognitive training. Still, to date no study has investigated the effect of varying the frequency of training on cognitive outcomes. Here we utilized a verbal memory based language learning task, tapping into implicit cognitive processes, to investigate the role of training intensity on learning rates in individuals with schizophrenia. Data from 47 participants across two studies was utilized, one with a daily training regimen over 5 days and the other with a more intensive schedule of 5 sessions delivered over 2 days. The primary outcome measure was the change in implicit learning performance across five sessions, quantified with the Matthews Correlation Coefficient (MCC). Participants in the daily training group showed improved performance compared to the intensive group only at session 4. This is the first study to show that implicit learning rates are influenced by training intensity, with daily sessions outperforming a more intensive regimen; a period of consolidation overnight may be necessary to optimize cognitive training for individuals with schizophrenia.

Real-time fMRI neurofeedback to down-regulate superior temporal gyrus activity in patients with schizophrenia and auditory hallucinations: a proof-of-concept study.

Neurocognitive models and previous neuroimaging work posit that auditory verbal hallucinations (AVH) arise due to increased activity in speech-sensitive regions of the left posterior superior temporal gyrus (STG). Here, we examined if patients with schizophrenia (SCZ) and AVH could be trained to down-regulate STG activity using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF). We also examined the effects of rtfMRI-NF training on functional connectivity between the STG and other speech and language regions. Twelve patients with SCZ and treatment-refractory AVH were recruited to participate in the study and were trained to down-regulate STG activity using rtfMRI-NF, over four MRI scanner visits during a 2-week training period. STG activity and functional connectivity were compared pre- and post-training. Patients successfully learnt to down-regulate activity in their left STG over the rtfMRI-NF training. Post- training, patients showed increased functional connectivity between the left STG, the left inferior prefrontal gyrus (IFG) and the inferior parietal gyrus. The post-training increase in functional connectivity between the left STG and IFG was associated with a reduction in AVH symptoms over the training period. The speech-sensitive region of the left STG is a suitable target region for rtfMRI-NF in patients with SCZ and treatment-refractory AVH. Successful down-regulation of left STG activity can increase functional connectivity between speech motor and perception regions. These findings suggest that patients with AVH have the ability to alter activity and connectivity in speech and language regions, and raise the possibility that rtfMRI-NF training could present a novel therapeutic intervention in SCZ.

Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia.

Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The 'real' and 'sham' groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.

Stimulating cognition in schizophrenia: A controlled pilot study of the effects of prefrontal transcranial direct current stimulation upon memory and learning.

BACKGROUND: Schizophrenia is characterized by prominent cognitive deficits, impacting on memory and learning; these are strongly associated with the prefrontal cortex. OBJECTIVE/HYPOTHESIS: To combine two interventions, transcranial direct current stimulation (tDCS) over the prefrontal cortex and cognitive training, to examine change in cognitive performance in patients with schizophrenia. METHODS: A double blind, sham-controlled pilot study of 49 patients with schizophrenia, randomized into real or sham tDCS stimulation groups. Subjects participated in 4 days of cognitive training (days 1, 2, 14, 56) with tDCS applied at day-1 and day-14. The primary outcome measure was change in accuracy on working memory and implicit learning tasks from baseline. The secondary outcome measure was the generalization of learning to non-trained task, indexed by the CogState neuropsychological battery. Data analysis was conducted using multilevel modelling and multiple regressions. RESULTS: 24 participants were randomized to real tDCS and 25 to sham. The working memory task demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 (b = 0.68, CI 0.14-1.21; p = 0.044) and at day-56 (b = 0.71, 0.16-1.26; p = 0.044). There were no significant effects of tDCS on implicit learning. Trend evidence of generalization onto untrained tasks of attention and vigilance task (b = 0.40, 0.43-0.77; p = 0.058) was found. CONCLUSIONS: This is the first study to show a significant longer-term effect of tDCS on working memory in schizophrenia. Given the current lack of effective therapies for cognitive deficits, tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia.

Interaction of language, auditory and memory brain networks in auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. However, reconciliation of these theories with experimental evidence is missing. We review 50 studies investigating functional (EEG and fMRI) and anatomic (diffusion tensor imaging) connectivity in these networks, and explore the evidence supporting abnormal connectivity in these networks associated with AVH. We distinguish between functional connectivity during an actual hallucination experience (symptom capture) and functional connectivity during either the resting state or a task comparing individuals who hallucinate with those who do not (symptom association studies). Symptom capture studies clearly reveal a pattern of increased coupling among the auditory, language and striatal regions. Anatomical and symptom association functional studies suggest that the interhemispheric connectivity between posterior auditory regions may depend on the phase of illness, with increases in non-psychotic individuals and first episode patients and decreases in chronic patients. Leading hypotheses involving concepts as unstable memories, source monitoring, top-down attention, and hybrid models of hallucinations are supported in part by the published connectivity data, although several caveats and inconsistencies remain. Specifically, possible changes in fronto-temporal connectivity are still under debate. Precise hypotheses concerning the directionality of connections deduced from current theoretical approaches should be tested using experimental approaches that allow for discrimination of competing hypotheses.