Dan W. Joyce

Functional Magnetic Resonance Imaging of Impaired Sensory Prediction in Schizophrenia

IMPORTANCE Forward models predict the sensory consequences of planned actions and permit discrimination of self- and non-self-elicited sensation; their impairment in schizophrenia is implied by an abnormality in behavioral force-matching and the flawed agency judgments characteristic of positive symptoms, including auditory hallucinations and delusions of control. OBJECTIVE To assess attenuation of sensory processing by self-action in individuals with schizophrenia and its relation to current symptom severity. DESIGN, SETTING, AND PARTICIPANTS Functional magnetic resonance imaging data were acquired while medicated individuals with schizophrenia (n = 19) and matched controls (n = 19) performed a factorially designed sensorimotor task in which the occurrence and relative timing of action and sensation were manipulated. The study took place at the neuroimaging research unit at the Institute of Cognitive Neuroscience, University College London, and the Maudsley Hospital. RESULTS In controls, a region of secondary somatosensory cortex exhibited attenuated activation when sensation and action were synchronous compared with when the former occurred after an unexpected delay or alone. By contrast, reduced attenuation was observed in the schizophrenia group, suggesting that these individuals were unable to predict the sensory consequences of their own actions. Furthermore, failure to attenuate secondary somatosensory cortex processing was predicted by current hallucinatory severity. CONCLUSIONS AND RELEVANCE Although comparably reduced attenuation has been reported in the verbal domain, this work implies that a more general physiologic deficit underlies positive symptoms of schizophrenia.

Spatial language, visual attention, and perceptual simulation

Spatial language descriptions, such as The bottle is over the glass, direct the attention of the hearer to particular aspects of the visual world. This paper asks how they do so, and what brain mechanisms underlie this process. In two experiments employing behavioural and eye tracking methodologies we examined the effects of spatial language on peoples judgements and parsing of a visual scene. The results underscore previous claims regarding the importance of object function in spatial language, but also show how spatial language differentially directs attention during examination of a visual scene. We discuss implications for existing models of spatial language, with associated brain mechanisms.

Modulation of somatosensory processing by action

Psychophysical evidence suggests that sensations arising from our own movements are diminished when predicted by motor forward models and that these models may also encode the timing and intensity of movement. Here we report a functional magnetic resonance imaging study in which the effects on sensation of varying the occurrence, timing and force of movements were measured. We observed that tactile-related activity in a region of secondary somatosensory cortex is reduced when sensation is associated with movement and further that this reduction is maximal when movement and sensation occur synchronously. Motor force is not represented in the degree of attenuation but rather in the magnitude of this regions response. These findings provide neurophysiological correlates of previously-observed behavioural forward-model phenomena, and advocate the adopted approach for the study of clinical conditions in which forward-model deficits have been posited to play a crucial role.

Aging effects on functional auditory and visual processing using fMRI with variable sensory loading

INTRODUCTION Traditionally, studies investigating the functional implications of age-related structural brain alterations have focused on higher cognitive processes; by increasing stimulus load, these studies assess behavioral and neurophysiological performance. In order to understand age-related changes in these higher cognitive processes, it is crucial to examine changes in visual and auditory processes that are the gateways to higher cognitive functions. This study provides evidence for age-related functional decline in visual and auditory processing, and regional alterations in functional brain processing, using non-invasive neuroimaging. METHODS Using functional magnetic resonance imaging (fMRI), younger (n=11; mean age=31) and older (n=10; mean age=68) adults were imaged while observing flashing checkerboard images (passive visual stimuli) and hearing word lists (passive auditory stimuli) across varying stimuli presentation rates. RESULTS Younger adults showed greater overall levels of temporal and occipital cortical activation than older adults for both auditory and visual stimuli. The relative change in activity as a function of stimulus presentation rate showed differences between young and older participants. In visual cortex, the older group showed a decrease in fMRI blood oxygen level dependent (BOLD) signal magnitude as stimulus frequency increased, whereas the younger group showed a linear increase. In auditory cortex, the younger group showed a relative increase as a function of word presentation rate, while older participants showed a relatively stable magnitude of fMRI BOLD response across all rates. When analyzing participants across all ages, only the auditory cortical activation showed a continuous, monotonically decreasing BOLD signal magnitude as a function of age. CONCLUSIONS Our preliminary findings show an age-related decline in demand-related, passive early sensory processing. As stimulus demand increases, visual and auditory cortex do not show increases in activity in older compared to younger people. This may negatively impact on the fidelity of information available to higher cognitive processing. Such evidence may inform future studies focused on cognitive decline in aging.

Amphetamine sensitization alters reward processing in the human striatum and amygdala.

Dysregulation of mesolimbic dopamine transmission is implicated in a number of psychiatric illnesses characterised by disruption of reward processing and goal-directed behaviour, including schizophrenia, drug addiction and impulse control disorders associated with chronic use of dopamine agonists. Amphetamine sensitization (AS) has been proposed to model the development of this aberrant dopamine signalling and the subsequent dysregulation of incentive motivational processes. However, in humans the effects of AS on the dopamine-sensitive neural circuitry associated with reward processing remains unclear. Here we describe the effects of acute amphetamine administration, following a sensitising dosage regime, on blood oxygen level dependent (BOLD) signal in dopaminoceptive brain regions during a rewarded gambling task performed by healthy volunteers. Using a randomised, double-blind, parallel-groups design, we found clear evidence for sensitization to the subjective effects of the drug, while rewarded reaction times were unchanged. Repeated amphetamine exposure was associated with reduced dorsal striatal BOLD signal during decision making, but enhanced ventromedial caudate activity during reward anticipation. The amygdala BOLD response to reward outcomes was blunted following repeated amphetamine exposure. Positive correlations between subjective sensitization and changes in anticipation- and outcome-related BOLD signal were seen for the caudate nucleus and amygdala, respectively. These data show for the first time in humans that AS changes the functional impact of acute stimulant exposure on the processing of reward-related information within dopaminoceptive regions. Our findings accord with pathophysiological models which implicate aberrant dopaminergic modulation of striatal and amygdala activity in psychosis and drug-related compulsive disorders.

Grounding language in perception: A connectionist model of spatial terms and vegue quantifiers

This paper presents a new connectionist model of spatial language based on real psycholinguistic data. It puts together various constraints on object knowledge (“what”) and on object localisation (“where”) in order to influence the comprehension of a range of linguistic terms, mirroring what participants do in experiments. The computational model consists of a vision processing module for input scenes, an Elman network module for the representation of object dynamics, and a dual-route network for the production of object names and linguistic prepositions describing the scene. Preliminary simulations on the prediction of spatial term ratings are presented, and extensions of the model to vague quantifiers and other syntactic categories are considered.

An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers

BACKGROUND Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. METHOD Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. RESULTS The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. CONCLUSION rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS.

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

Eluding the illusion?: Schizophrenia, dopamine and the McGurk effect

Perceptions are inherently probabilistic; and can be potentially manipulated to induce illusory experience by the presentation of ambiguous or improbable evidence under selective (spatio-temporal) constraints. Accordingly, perception of the McGurk effect, by which individuals misperceive specific incongruent visual and auditory vocal cues, rests upon effective probabilistic inference. Here, we report findings from a behavioral investigation of illusory perception and related metacognitive evaluation during audiovisual integration, conducted in individuals with schizophrenia (n = 30) and control subjects (n = 24) matched in terms of age, sex, handedness and parental occupation. Controls additionally performed the task after an oral dose of amisulpride (400 mg). Individuals with schizophrenia were observed to exhibit illusory perception less frequently than controls, despite non-significant differences in perceptual performance during control conditions. Furthermore, older individuals with schizophrenia exhibited reduced rates of illusory perception. Subsequent analysis revealed a robust inverse relationship between illness chronicity and the illusory perception rate in this group. Controls demonstrated non-significant modulation of perception by amisulpride; amisulpride was, however, found to elicit increases in subjective confidence in perceptual performance. Overall, these findings are consistent with the idea that impairments in probabilistic inference are exhibited in schizophrenia and exacerbated by illness chronicity. The latter suggests that associated processes are a potentially worthwhile target for therapeutic intervention.

Realising stratified psychiatry using multidimensional signatures and trajectories

AbstractBackground Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry.Methods and findingsTo achieve a truly ‘stratified psychiatry’ we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia—conceptualised as a label for heterogeneous disorders—as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal.ConclusionWe describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification.