Integrated neural dynamics for behavioural decisions and attentional competition in the prefrontal cortex.

In the behaving monkey, complex neural dynamics in the prefrontal cortex contribute to context-dependent decisions and attentional competition. We used demixed principal component analysis to track prefrontal activity dynamics in a cued target detection task. In this task, the animal combined identity of a visual object with a prior instruction cue to determine a target/nontarget decision. From population activity, we extracted principal components for each task feature and examined their time course and sensitivity to stimulus and task variations. For displays containing a single choice object in left or right hemifield, object identity, cue identity and decision were all encoded in population activity, with different dynamics and lateralisation. Object information peaked at 100-200 ms from display onset and was largely confined to the contralateral hemisphere. Cue information was weaker and present even prior to display onset. Integrating information from cue and object, decision information arose more slowly and was bilateral. Individual neurons contributed independently to coding of the three task features. The analysis was then extended to displays with a target in one hemifield and a competing distractor in the other. In this case, the data suggest that each hemisphere initially encoded the identity of the contralateral object. The distractor representation was then rapidly suppressed, with the final target decision again encoded bilaterally. The results show how information is coded along task-related dimensions while competition is resolved and suggest how information flows within and across frontal lobes to implement a learned behavioural decision.

Representational Account of Memory: Insights from Aging and Synesthesia.

The representational account of memory envisages perception and memory to be on a continuum rather than in discretely divided brain systems [Bussey, T. J., & Saksida, L. M. Memory, perception, and the ventral visual-perirhinal-hippocampal stream: Thinking outside of the boxes. Hippocampus, 17, 898-908, 2007]. We tested this account using a novel between-group design with young grapheme-color synesthetes, older adults, and young controls. We investigated how the disparate sensory-perceptual abilities between these groups translated into associative memory performance for visual stimuli that do not induce synesthesia. ROI analyses of the entire ventral visual stream showed that associative retrieval (a pair-associate retrieved in the absence of a visual stimulus) yielded enhanced activity in young and older adults' visual regions relative to synesthetes, whereas associative recognition (deciding whether a visual stimulus was the correct pair-associate) was characterized by enhanced activity in synesthetes' visual regions relative to older adults. Whole-brain analyses at associative retrieval revealed an effect of age in early visual cortex, with older adults showing enhanced activity relative to synesthetes and young adults. At associative recognition, the group effect was reversed: Synesthetes showed significantly enhanced activity relative to young and older adults in early visual regions. The inverted group effects observed between retrieval and recognition indicate that reduced sensitivity in visual cortex (as in aging) comes with increased activity during top-down retrieval and decreased activity during bottom-up recognition, whereas enhanced sensitivity (as in synesthesia) shows the opposite pattern. Our results provide novel evidence for the direct contribution of perceptual mechanisms to visual associative memory based on the examples of synesthesia and aging.

Spatial and temporal distribution of visual information coding in lateral prefrontal cortex.

Prefrontal neurons code many kinds of behaviourally relevant visual information. In behaving monkeys, we used a cued target detection task to address coding of objects, behavioural categories and spatial locations, examining the temporal evolution of neural activity across dorsal and ventral regions of the lateral prefrontal cortex (encompassing parts of areas 9, 46, 45A and 8A), and across the two cerebral hemispheres. Within each hemisphere there was little evidence for regional specialisation, with neurons in dorsal and ventral regions showing closely similar patterns of selectivity for objects, categories and locations. For a stimulus in either visual field, however, there was a strong and temporally specific difference in response in the two cerebral hemispheres. In the first part of the visual response (50-250 ms from stimulus onset), processing in each hemisphere was largely restricted to contralateral stimuli, with strong responses to such stimuli, and selectivity for both object and category. Later (300-500 ms), responses to ipsilateral stimuli also appeared, many cells now responding more strongly to ipsilateral than to contralateral stimuli, and many showing selectivity for category. Activity on error trials showed that late activity in both hemispheres reflected the animal's final decision. As information is processed towards a behavioural decision, its encoding spreads to encompass large, bilateral regions of prefrontal cortex.

Treatment outcomes in the inpatient management of severe functional neurological disorder: a retrospective cohort study.

Background: Functional neurological disorder (FND) is a heterogeneous condition; severe forms can be disabling. Multidisciplinary treatment and rehabilitation are recommended for severe FND, but there remains a lack of evidence for its efficacy and lack of understanding of the predictors and components of recovery. Methods: We report clinical outcome data for an inpatient cohort with severe FND. Clinical Global Impression Improvement with treatment is the primary outcome measure. Admission and discharge measures (Euroqol quality of life measures, Beck Depression Inventory, Spielberger Trait Anxiety Inventory, Cambridge Depersonalisation Scale, Illness Perception Questionnaire (Revised) and Functional Mobility Scale) are reported as secondary outcomes. Results: We describe an FND cohort (n=52) with chronic illness (mean symptom duration 9.7 years). At admission, there were clinically relevant levels of depression, anxiety and depersonalisation derealisation. At the time of discharge, most (43/52) patients' global condition had improved. Measures of mobility, depression and quality of life also significantly improved while at discharge, symptoms were experienced as more understandable and less distressing than at admission. An admission measure of patient confidence in treatment was predictive of eventual clinical outcome. Conclusions: The most frequent outcome of inpatient rehabilitation is global improvement, even when symptoms are chronic and severe, reflected in measurable changes in both physical and psychological functioning. Significant levels of depersonalisation derealisation seen in this patient group suggest that routine enquiry into such experiences could help personalise FND treatment approaches. Patient confidence in treatment is key in determining clinical outcomes.

Case report: Clinical lycanthropy in Huntington's disease.

We describe the case of a patient diagnosed with Huntington's disease (HD), who, following a two-year history of anxiety with obsessional preoccupations, developed psychosis with clinical lycanthropy: a prominent delusional idea that he was a werewolf. Although there was no benefit from various antidepressants and antipsychotics, there was remarkable improvement of his symptoms following prescription of Clozapine. His choreiform movement disorder also improved as his mental state settled. Although some reported cases of clinical lycanthropy are related to neurological conditions, this is the first case in a patient with HD. We also discuss the relevance of cultural and personal factors in the expression of a delusion that incorporates disgust, and the potential role of somatosensory aberrations and misidentification of self.

The effect of treatment on insight in psychotic disorders - A systematic review and meta-analysis.

BACKGROUND: For people with a psychotic disorder lack of insight can be detrimental on their condition and recovery. For this reason, insight has been considered as a target for therapy. We conducted a systematic review of the literature on pharmacological, psychological and other treatments to test the hypothesis that these interventions could improve insight. METHODS: We performed a literature search (1970-2020) across the following databases: PubMed, EMBASE, PsychINFO, Medline and Web of Science. Within each database the following search terms and the associated Boolean operatives were used: "Insight AND (treatment OR therapy) AND (psychosis OR schizophrenia) AND (awareness or denial)". Further filters were applied to identify peer reviewed controlled trials on adults. Following assessment for bias and inclusion criteria, we calculated the effect size (Cohen's d) for each study and overall, using a random effects model with 95% confidence intervals. RESULTS: Of 94 articles found in the initial literature search, 30 studies that examined the treatment of insight in psychosis met the initial selection criteria and were assessed for bias. A total of 21 studies were included in the final meta-analysis. The overall calculated mean effect size for all interventions was 0.441 (95% CI, 0.23-0.66), representing a medium effect size. The effect of psychoeducation studies alone was medium (0.613, 95% CI, -0.35-2.06), but not significant. The effect of CBT studies was small (0.235, 95% CI, 0.01-0.46), and significant. The effect of combined antipsychotic medication and psychosocial intervention was of medium size and significant (0.683, 95% CI = 0.54-0.83). Finally, tDCS over the left fronto-temporal cortex, produced a very large and significant improvement of insight 1.153 (95% CI = 0.61-1.70), which was present for at least a month after the intervention. CONCLUSIONS: Despite the variation and small number and size of trials into possible interventions, the hypothesis that insight could be improved was confirmed. Whilst most research focuses on psychotherapies, there is scope and potential for pharmacological, as well as other interventions (e.g. physical exercise, self-video observation, Direct Current Stimulation) to improve insight over and above treatment as usual. Given the association of insight with illness severity and treatment adherence, it is important to direct efforts in therapies that target insight improvement in psychosis.

Hierarchical coding for sequential task events in the monkey prefrontal cortex.

The frontal lobes play a key role in sequential organization of behavior. Little is known, however, of the way frontal neurons code successive phases of a structured task plan. Using correlational analysis, we asked how a population of frontal cells represents the multiple events of a complex sequential task. Monkeys performed a conventional cue-target association task, with distinct cue, delay, and target phases. Across the population of recorded cells, we examined patterns of activity for different task phases, and in the same phase, for different stimulus objects. The results show hierarchical representation of task events. For different task phases, there were different, approximately orthogonal patterns of activity across the population of neurons. Modulations of each basic pattern encoded stimulus information within each phase. By orthogonal coding, the frontal lobe may control transitions between the discrete steps of a mental program; by correlated coding within each step, similar operations may be applied to different stimulus content.

Target detection by opponent coding in monkey prefrontal cortex.

The pFC plays a key role in flexible, context-specific decision making. One proposal [Machens, C. K., Romo, R., & Brody, C. D. Flexible control of mutual inhibition: A neural model of two-interval discrimination. Science, 307, 1121-1124, 2005] is that prefrontal cells may be dynamically organized into opponent coding circuits, with competitive groups of cells coding opposite behavioral decisions. Here, we show evidence for extensive, temporally evolving opponent organization in the monkey pFC during a cued target detection task. More than a half of all randomly selected cells discriminated stimulus category in this task. The largest set showed target-positive activity, with the strongest responses to the current target, intermediate activity for a nontarget that was a target on other trials, and lowest activity for nontargets never associated with the target category. Second most frequent was a reverse, antitarget pattern. In the ventrolateral frontal cortex, opponent organization was strongly established in phasic responses at stimulus onset; later, such activity was widely spread across dorsolateral and ventrolateral sites. Task-specific organization into opponent cell groups may be a general feature of prefrontal decision making.

Detection of fixed and variable targets in the monkey prefrontal cortex.

Behavioral significance is commonly coded by prefrontal neurons. The significance of a stimulus can be fixed through experience; in complex behavior, however, significance commonly changes with short-term context. To compare these cases, we trained monkeys in 2 versions of visual target detection. In both tasks, animals monitored a series of pictures, making a go response (saccade) at the offset of a specified target picture. In one version, based on "consistent mapping" in human visual search, target and nontarget pictures were fixed throughout training. In the other, based on "varied mapping," a cue at trial onset defined a new target. Building up over the first 1 s following this cue, many cells coded short-term context (cue/target identity) for the current trial. Thereafter, the cell population showed similar coding of behavioral significance in the 2 tasks, with selective early response to targets, and later, sustained activity coding target or nontarget until response. This population similarity was seen despite quite different activity in the 2 tasks for many single cells. At the population level, the results suggest similar prefrontal coding of fixed and short-term behavioral significance.

Reduced Visual and Frontal Cortex Activation During Visual Working Memory in Grapheme-Color Synaesthetes Relative to Young and Older Adults.

The sensory recruitment model envisages visual working memory (VWM) as an emergent property that is encoded and maintained in sensory (visual) regions. The model implies that enhanced sensory-perceptual functions, as in synaesthesia, entail a dedicated VWM-system, showing reduced visual cortex activity as a result of neural specificity. By contrast, sensory-perceptual decline, as in old age, is expected to show enhanced visual cortex activity as a result of neural broadening. To test this model, young grapheme-color synaesthetes, older adults and young controls engaged in a delayed pair-associative retrieval and a delayed matching-to-sample task, consisting of achromatic fractal stimuli that do not induce synaesthesia. While a previous analysis of this dataset (Pfeifer et al., 2016) has focused on cued retrieval and recognition of pair-associates (i.e., long-term memory), the current study focuses on visual working memory and considers, for the first time, the crucial delay period in which no visual stimuli are present, but working memory processes are engaged. Participants were trained to criterion and demonstrated comparable behavioral performance on VWM tasks. Whole-brain and region-of-interest-analyses revealed significantly lower activity in synaesthetes' middle frontal gyrus and visual regions (cuneus, inferior temporal cortex), respectively, suggesting greater neural efficiency relative to young and older adults in both tasks. The results support the sensory recruitment model and can explain age and individual WM-differences based on neural specificity in visual cortex.

The neural mechanisms of object working memory: what is where in the infant brain?

The question of how representational capacities develop in humans has been engaging cognitive psychologists for decades. Looking time studies have explored when infants start to show signs of perceiving and remembering the properties of specific objects at specific locations. Here we integrate these findings into the neuroscientific framework of human visual working memory. We suggest that the development of a system involving the temporal cortex, thalamic and hippocampal structures and possibly the dorsolateral prefrontal cortex (later in development) can account for these behavioral results. Our explanation differs from most of the current approaches in developmental science as we put less emphasis on the contribution of lateral prefrontal areas. We discuss shortcomings of the theories that propose a functional subdivision of these areas and their difficulty in accounting for results from monkey lesion and infant studies. We believe that this shift in focus is desirable both in light of what recent results on medial temporal lobe processing reveal about object working memory, and given how well these results fit the behavioral developmental data.

Visual categorization and the inferior temporal cortex.

We investigated the effects of categorization on the representation of stimulus features in combined psychophysical-electrophysiological experiments. We used parameterized line drawings of faces and fish as stimuli, and we varied the relevance of the different features for the categorization task. The psychophysical and electrophysiological data support an exemplar-based framework for visual object recognition. We recorded from visual neurons in the anterior inferior temporal (IT) cortex of macaque monkeys, while they were performing a categorization task. The visual neurons did not respond selectively to one stimulus set, or to one category. The majority of the anterior IT feature selective neurons were tuned for features that were diagnostic for the categorization task. We argue that this fine-tuning of the neurons reflects the perceptual sensitization to the diagnostic features.

Associative memory advantage in grapheme-color synesthetes compared to older, but not young adults.

People with grapheme-color synesthesia perceive enriched experiences of colors in response to graphemes (letters, digits). In this study, we examined whether these synesthetes show a generic associative memory advantage for stimuli that do not elicit a synesthetic color. We used a novel between group design (14 young synesthetes, 14 young, and 14 older adults) with a self-paced visual associative learning paradigm and subsequent retrieval (immediate and delayed). Non-synesthesia inducing, achromatic fractal pair-associates were manipulated in visual similarity (high and low) and corresponded to high and low memory load conditions. The main finding was a learning and retrieval advantage of synesthetes relative to older, but not to younger, adults. Furthermore, the significance testing was supported with effect size measures and power calculations. Differences between synesthetes and older adults were found during dissimilar pair (high memory load) learning and retrieval at immediate and delayed stages. Moreover, we found a medium size difference between synesthetes and young adults for similar pair (low memory load) learning. Differences between young and older adults were also observed during associative learning and retrieval, but were of medium effect size coupled with low power. The results show a subtle associative memory advantage in synesthetes for non-synesthesia inducing stimuli, which can be detected against older adults. They also indicate that perceptual mechanisms (enhanced in synesthesia, declining as part of the aging process) can translate into a generic associative memory advantage, and may contribute to associative deficits accompanying healthy aging.

Effective connectivity reveals strategy differences in an expert calculator.

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of "cortical hubs" supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material.

Dynamic coding for cognitive control in prefrontal cortex.

Cognitive flexibility is fundamental to adaptive intelligent behavior. Prefrontal cortex has long been associated with flexible cognitive function, but the neurophysiological principles that enable prefrontal cells to adapt their response properties according to context-dependent rules remain poorly understood. Here, we use time-resolved population-level neural pattern analyses to explore how context is encoded and maintained in primate prefrontal cortex and used in flexible decision making. We show that an instruction cue triggers a rapid series of state transitions before settling into a stable low-activity state. The postcue state is differentially tuned according to the current task-relevant rule. During decision making, the response to a choice stimulus is characterized by an initial stimulus-specific population response but evolves to different final decision-related states depending on the current rule. These results demonstrate how neural tuning profiles in prefrontal cortex adapt to accommodate changes in behavioral context. Highly flexible tuning could be mediated via short-term synaptic plasticity.

Dynamic construction of a coherent attentional state in a prefrontal cell population.

Prefrontal cortex has been proposed to show highly adaptive information coding, with neurons dynamically allocated to processing task-relevant information. To track this dynamic allocation in monkey prefrontal cortex, we used time-resolved measures of neural population activity in a simple case of competition between target (behaviorally critical) and nontarget objects in opposite visual hemifields. Early in processing, there were parallel responses to competing inputs, with neurons in each hemisphere dominated by the contralateral stimulus. Later, the nontarget lost control of neural activity, with emerging global control by the behaviorally critical target. The speed of transition reflected the competitive weights of different display elements, occurring most rapidly when relative behavioral significance was well established by training history. In line with adaptive coding, the results show widespread reallocation of prefrontal processing resources as an attentional focus is established.

An analysis approach for high-field fMRI data from awake non-human primates.

fMRI experiments with awake non-human primates (NHP) have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1) Trial-based experimental design. 2) Careful control of subject movement. 3) Computer-assisted selection of trials devoid of artefacts and animal motion. 4) Nonrigid between-trial and rigid within-trial realignment of concatenated data from temporally separated trials and sessions. 5) Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6) Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri-sandbox/), for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan.

Realignment strategies for awake-monkey fMRI data.

Functional magnetic resonance imaging (fMRI) experiments with awake nonhuman primates (NHPs) have recently seen a surge of applications. However, the standard fMRI analysis tools designed for human experiments are not optimal for NHP data collected at high fields. One major difference is the experimental setup. Although real head movement is impossible for NHPs, MRI image series often contain visible motion artifacts. Animal body movement results in image position changes and geometric distortions. Since conventional realignment methods are not appropriate to address such differences, algorithms tailored specifically for animal scanning become essential. We have implemented a series of high-field NHP specific methods in a software toolbox, fMRI Sandbox (http://kyb.tuebingen.mpg.de/~stoewer/), which allows us to use different realignment strategies. Here we demonstrate the effect of different realignment strategies on the analysis of awake-monkey fMRI data acquired at high field (7 T). We show that the advantage of using a nonstandard realignment algorithm depends on the amount of distortion in the dataset. While the benefits for less distorted datasets are minor, the improvement of statistical maps for heavily distorted datasets is significant.