Dopamine D2 receptor stimulation modulates the balance between ignoring and updating according to baseline working memory ability

BACKGROUND:Working memory (WM) deficits in neuropsychiatric disorders have often been attributed to altered dopaminergic signalling. Specifically, D2 receptor stimulation is thought to affect the ease with which items can be gated into and out of WM. In addition, this effect has been hypothesised to vary according to baseline WM ability, a putative index of dopamine synthesis levels. Moreover, whether D2 stimulation affects WM vicariously through modulating relatively WM-free cognitive control processes has not been explored. AIMS:We examined the effect of administering a dopamine agonist on the ability to ignore or update information in WM. METHOD:A single dose of cabergoline (1 mg) was administered to healthy older adult humans in a within-subject, double-blind, placebo-controlled study. In addition, we obtained measures of baseline WM ability and relatively WM-free cognitive control (overcoming response conflict). RESULTS:Consistent with predictions, baseline WM ability significantly modulated the effect that drug administration had on the proficiency of ignoring and updating. High-WM individuals were relatively better at ignoring compared to updating after drug administration. Whereas the opposite occurred in low-WM individuals. Although the ability to overcome response conflict was not affected by cabergoline, a negative relationship between the effect the drug had on response conflict performance and ignoring was observed. Thus, both response conflict and ignoring are coupled to dopaminergic stimulation levels. CONCLUSIONS:Cumulatively, these results provide evidence that dopamine affects subcomponents of cognitive control in a diverse, antagonistic fashion and that the direction of these effects is dependent upon baseline WM

The selective updating of working memory: a predictive coding account

Goal-relevant information maintained in working memory is remarkably robust and resistant to distractions. However, our nervous system is endowed with exceptional flexibility; therefore such information can be updated almost effortlessly. A scenario – not uncommon in our daily life – is that selective maintaining and updating information can be achieved concurrently. This is an intriguing example of how our brain balances stability and flexibility, when organising its knowledge. A possibility – one may draw upon to understand this capacity – is that working memory is represented as beliefs, or its probability densities, which are updated in a context-sensitive manner. This means one could treat working memory in the same way as perception – i.e., memories are based on inferring the cause of sensations, except that the time scale ranges from an instant to prolonged anticipation. In this setting, working memory is susceptible to prior information encoded in the brain’s model of its world. This thesis aimed to establish an interpretation of working memory processing that rests on the (generalised) predictive coding framework, or hierarchical inference in the brain. Specifically, the main question it asked was how anticipation modulates working memory updating (or maintenance). A novel working memory updating task was designed in this regard. Blood-oxygen-level dependent (BOLD) imaging, machine learning, and dynamic causal modelling (DCM) were applied to identify the neural correlates of anticipation and the violation of anticipation, as well as the causal structure generating these neural correlates. Anticipation induced neural activity in the dopaminergic midbrain and the striatum. Whereas, the fronto-parietal and cingulo-operculum network were implicated when an anticipated update was omitted, and the midbrain, occipital cortices, and cerebellum when an update was unexpected. DCM revealed that anticipation is a modulation of backward connections, whilst the associated surprise is mediated by forward and local recurrent modulations. Two mutually antagonistic pathways were differentially modulated under anticipatory flexibility and stability, respectively. The overall results indicate that working memory may as well follow the cortical message-passing scheme that enables hierarchical inference

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia

Verbal working memory and functional large-scale networks in schizophrenia

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia

Striatal Activity is Associated with Deficits of Cognitive Control and Aberrant Salience for Patients with Schizophrenia

A recent study has shown that the locus of the largest known dopamine abnormality between patients with schizophrenia and healthy controls is in the associative striatum (Kegeles et al., 2010). This dopamine abnormality in the associative striatum is thought to bring about aberrant salience assignment for patients, which may underlie symptoms of psychosis like delusions and hallucinations (Howes & Kapur, 2009). Interestingly, the associative striatum has segregated, looped, connectivity with cortical regions including the prefrontal and parietal cortices (Draganski et al., 2008; Redgrave, Vautrelle, & Reynolds, 2011) and computational models have suggested that it may function as an information gate during cognitive control (Frank, Loughry, & O\u27Reilly, 2001; Gruber, Dayan, Gutkin, & Solla, 2006), much the way that posterior portions of the striatum gate motor control (Chevalier & Deniau, 1990). The current study sought to explore the relationship between striatal involvement in cognition and aberrant salience symptom expression using a novel task of cognitive control. We examined aberrant salience using a self-report measure (Cicero et al., 2010) and core components of cognitive control (updating, interference control, and simple maintenance), that are critically reliant on intact information gating, in a sample of 22 patients with schizophrenia and 20 healthy controls using a slow event-related fMRI design. We predicted that 1) aberrant salience symptoms would be greater for patients than controls, 2) that patients would demonstrate increased errors during interference controls trials, given that patients may be inappropriately assigning salience to distracters, and 3) that striatal activity during those errors could be positively correlated with aberrant salience symptoms. We found a trend toward significant differences between patients and controls on aberrant salience symptom presence, and a significant difference between groups during updating performance. During interference control trials, although we found no difference between groups when participants were tasked with maintaining targets during distracter presentation, patients were more likely to make errors when probed with those distracters, suggesting inappropriate distracter updating. When examining the brain activity during correct and incorrect updating and interference control trials, for patients update trial activity in the prefrontal cortex and striatum was significantly lower for incorrect updating trials when compared to correct updating trials, and significantly greater when patients inappropriately identified the distracter as correct compared with trials when they correctly rejected the distracter. Activity did not differ between correct and incorrect updating or interference control trials for controls. Further, we found that for patients, as predicted, the increase of activity during incorrect distracter trials was positively correlated with aberrant salience symptoms, but only for the associative striatal region and not the prefrontal region. We found no relationship between aberrant salience and patient brain activity during correct distracter trials, nor did we find significant relationships between aberrant salience and brain activity during either updating or interference control trials for controls. These results demonstrate that cognitive control deficits of patients demonstrate some domain selectivity, given that we found some evidence for preserved simple maintenance and maintenance in the face of task relevant distracter performance, but impaired performance at updating and ignoring distracters. Finally, we found evidence demonstrating a relationship between aberrant salience symptom expression for patients, cognitive deficits, and associative striatal activity. This relationship may have implications for treatments that improve cognitive function and reduce symptom expression

Spatio-Temporal Neural Changes After Task-Switching Training in Old Age

In the present study, we aimed at examining selective neural changes after taskswitching training in old age by not only considering the spatial location but also the timescale of brain activation changes (i.e., sustained/block-related or transient/trialrelated timescales). We assigned a sample of 50 older adults to a task-switching training or an active single-task control group. We administered two task paradigms, either sensitive to transient (i.e., a context-updating task) or sustained (i.e., a delayedrecognition working-memory task) dynamics of cognitive control. These dynamics were captured by utilizing an appropriate event-related or block-related functional magnetic resonance imaging design. We captured selective changes in task activation during the untrained tasks after task-switching training compared to an active control group. Results revealed changes at the neural level that were not evident from only behavioral data. Importantly, neural changes in the transient-sensitive context updating task were found on the same timescale but in a different region (i.e., in the left inferior parietal lobule) than in the task-switching training task (i.e., ventrolateral PFC, inferior frontal junction, superior parietal lobule), only pointing to temporal overlap, while neural changes in the sustained-sensitive delayed-recognition task overlapped in both timescale and region with the task-switching training task (i.e., in the basal ganglia), pointing to spatio-temporal overlap. These results suggest that neural changes after task-switching training seem to be critically supported by the temporal organization of neural processing.Deutsche Forschungsgemeinschaft (DFG

Neural and Behavioral Mechanisms of Interval Timing in the Striatum

To guide behavior and learn from its consequences, the brain must represent time over many scales. Yet, the neural signals used to encode time in the seconds to minute range are not known. The striatum is the major input area of the basal ganglia; it plays important roles in learning, motor function and normal timing behavior in the range of seconds to minutes. We investigated how striatal population activity might encode time. To do so, we recorded the electrical activity from striatal neurons in rats performing the serial fixed interval task, a dynamic version of the fixed Interval schedule of reinforcement. The animals performed in conformity with proportional timing, but did not strictly conform to scalar timing predictions, which might reflect a parallel strategy to optimize the adaptation to changes in temporal contingencies and consequently to improve reward rate over the session. Regarding the neural activity, we found that neurons fired at delays spanning tens of seconds and that this pattern of responding reflected the interaction between time and the animals’ ongoing sensorimotor state. Surprisingly, cells rescaled responses in time when intervals changed, indicating that striatal populations encoded relative time. Moreover, time estimates decoded from activity predicted trial-bytrial timing behavior as animals adjusted to new intervals, and disrupting striatal function with local infusion of muscimol led to a decrease in timing performance. Because of practical limitations in testing for sufficiency a biological system, we ran a simple simulation of the task; we have shown that neural responses similar to those we observe are conceptually sufficient to produce temporally adaptive behavior. Furthermore, we attempted to explain temporal processes on the basis of ongoing behavior by decoding temporal estimates from high-speed videos of the animals performing the task; we could not explain the temporal report solely on basis of ongoing behavior. These results suggest that striatal activity forms a scalable population firing rate code for time, providing timing signals that animals use to guide their actions

Investigation into functional large-scale networks in individuals with schizophrenia using fMRI data and Dynamic Causal Modelling

Schizophrenia is a complex and severe psychiatric disorder with positive symptoms, negative symptoms and cognitive deficits. Preclinical neurobiological studies showed that alterations of dopaminergic and glutamatergic neurotransmitter circuits involving the prefrontal cortex resulted in cognitive impairment such as working memory. Functional activation and functional connectivity findings of functional Magnetic Resonance Imaging (fMRI) data provided support for prefrontal dysfunction during fMRI working memory tasks in individuals with schizophrenia. However, these findings do not offer a neurobiological interpretation of the fMRI data. Biophysical modelling of functional large-scale networks has been designed for the analysis of fMRI data, which can be interpreted in a mechanistic way. This approach may enable the interpretation of fMRI data in terms of altered synaptic plasticity processes found in schizophrenia. One such process is gating mechanism, which has been shown to be altered for the thalamo-cortical and meso-cortical connection in schizophrenia. The primary aim of the thesis was to investigate altered synaptic plasticity and gating mechanisms with Dynamic Causal Modelling (DCM) within functional large-scale networks during two fMRI tasks in individuals with schizophrenia. Applying nonlinear DCM to the verbal fluency fMRI task of the Edinburgh High Risk Study, we showed that the connection strengths with nonlinear modulation for the thalamo-cortical connection was reduced in subjects at high familial risk of schizophrenia when compared to healthy controls. These results suggest that nonlinear DCM enables the investigation of altered synaptic plasticity and gating mechanism from fMRI data. For the Scottish Family Mental Health Study, we reported two different optimal linear models for individuals with established schizophrenia (EST) and healthy controls during working memory function. We suggested that this result may indicate that EST and healthy controls used different functional large-scale networks. The results of nonlinear DCM analyses may suggest that gating mechanism was intact in EST and healthy controls. In conclusion, the results presented in this thesis give evidence for the role of synaptic plasticity processes as assessed in functional large-scale networks during cognitive tasks in individuals with schizophrenia

Cognitive therapy, working memory training, and the treatment of Methamphetamine Use Disorder - a functional MRI study

Background: In recent years, methamphetamine use disorder (MUD), which is associated with adverse outcomes and represents a significant public health burden, has become highly prevalent in Cape Town, South Africa. Protracted methamphetamine (MA) use has been linked with neural dysfunction and working memory deficits. Although current treatments have shown limited efficacy in addressing MUD, recent evidence indicates the potential of utilizing tailored brief cognitive therapy programs and working memory training to improve outcomes. The current study aims to investigate the potential impact of brief cognitive therapy and using working memory training as an adjunct in the treatment of MUD. Methods: Participants were recruited from an in-patient drug rehabilitation centre in Cape Town. The sample (n = 26) consists of male patients (between the ages of 18–50) diagnosed with MUD. MUD patients were randomly split into 2 groups that received 4 weeks of treatment, i.e. treatment as usual (cognitive therapy only (NT) (n= 12)) and cognitive therapy with working memory training (CT) (n = 14). Neuroimaging and psychological data were collected from participants pre- and post- intervention to assess the relative impact of said interventions. Results: Behavioural outcome measures and the n-back working memory task adapted for fMRI were measured and compared pre- and post- intervention. No significant differences were present between groups prior treatment on behavioural measures, demographic measures, and fMRI activity. The brief cognitive therapy appeared to reduce depression and impulsivity scores over the course of the intervention, with scores slightly lower in the CT group. An FDR corrected whole-brain repeated measures ANOVA on the main effect of group indicated significant activation in the left posterior cingulate, left anterior cingulate, and left lingual gyrus. Post hoc t-tests were then conducted to follow up the group main effect and significant differences under FDR correction were observed in the NT group (in contrast to the CT group) indicating significantly more activity in the left superior temporal gyrus, left insula, right posterior declive, and right lingual gyrus. Significant differences were also observed under FDR correction on a posthoc test on the CT group (in contrast to the NT group) indicating significantly less activity in the left lingual gyrus, left posterior declive, and right cuneus. 5 Conclusions: The findings tentatively suggest that the working memory training adjunct may have slightly enhanced working memory maintenance brain function relative to the treatment as usual group post-intervention. The evidence also suggests that there may have been inefficient neural functioning in the treatment as usual group during the working memory task compared to the group receiving the working memory training adjunct. The results demonstrated that brief cognitive therapy treatment did somewhat reduce depressive symptoms and impulsivity in this study, with indications of subtle treatment gains in the cognitive training group. Overall, the current study (despite numerous limitations) provides preliminary and tentative evidence of the possible benefits of brief term cognitive therapy and the potential promise of using working memory training as a treatment adjunct