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1.
Psychopharmacology (Berl) ; 239(6): 1809-1821, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35507071

ABSTRACT

Renewed interest in psychedelics has reignited the debate about whether and how they change human beliefs. In both the clinical and social-cognitive domains, psychedelic consumption may be accompanied by profound, and sometimes lasting, belief changes. We review these changes and their possible underlying mechanisms. Rather than inducing de novo beliefs, we argue psychedelics may instead change the impact of affect and of others' suggestions on how beliefs are imputed. Critically, we find that baseline beliefs (in the possible effects of psychedelics, for example) might color the acute effects of psychedelics as well as longer-term changes. If we are to harness the apparent potential of psychedelics in the clinic and for human flourishing more generally, these possibilities must be addressed empirically.


Subject(s)
Hallucinogens , Hallucinogens/pharmacology , Hallucinogens/therapeutic use , Humans
2.
Science ; 357(6351): 596-600, 2017 08 11.
Article in English | MEDLINE | ID: mdl-28798131

ABSTRACT

Some people hear voices that others do not, but only some of those people seek treatment. Using a Pavlovian learning task, we induced conditioned hallucinations in four groups of people who differed orthogonally in their voice-hearing and treatment-seeking statuses. People who hear voices were significantly more susceptible to the effect. Using functional neuroimaging and computational modeling of perception, we identified processes that differentiated voice-hearers from non-voice-hearers and treatment-seekers from non-treatment-seekers and characterized a brain circuit that mediated the conditioned hallucinations. These data demonstrate the profound and sometimes pathological impact of top-down cognitive processes on perception and may represent an objective means to discern people with a need for treatment from those without.


Subject(s)
Brain/physiology , Conditioning, Classical , Hallucinations/psychology , Perception , Acoustic Stimulation , Adult , Computer Simulation , Female , Hallucinations/physiopathology , Hearing , Humans , Male , Models, Neurological , Nerve Net , Neuroimaging , Photic Stimulation , Psychotic Disorders/physiopathology , Psychotic Disorders/psychology , Voice
3.
Psychol Med ; 46(12): 2605-15, 2016 09.
Article in English | MEDLINE | ID: mdl-27353541

ABSTRACT

BACKGROUND: Language use is of increasing interest in the study of mental illness. Analytical approaches range from phenomenological and qualitative to formal computational quantitative methods. Practically, the approach may have utility in predicting clinical outcomes. We harnessed a real-world sample (blog entries) from groups with psychosis, strong beliefs, odd beliefs, illness, mental illness and/or social isolation to validate and extend laboratory findings about lexical differences between psychosis and control subjects. METHOD: We describe the results of two experiments using Linguistic Inquiry and Word Count software to assess word category frequencies. In experiment 1, we compared word use in psychosis and control subjects in the laboratory (23 per group), and related results to subject symptoms. In experiment 2, we examined lexical patterns in blog entries written by people with psychosis and eight comparison groups. In addition to between-group comparisons, we used factor analysis followed by clustering to discern the contributions of strong belief, odd belief and illness identity to lexical patterns. RESULTS: Consistent with others' work, we found that first-person pronouns, biological process words and negative emotion words were more frequent in psychosis language. We tested lexical differences between bloggers with psychosis and multiple relevant comparison groups. Clustering analysis revealed that word use frequencies did not group individuals with strong or odd beliefs, but instead grouped individuals with any illness (mental or physical). CONCLUSIONS: Pairing of laboratory and real-world samples reveals that lexical markers previously identified as specific language changes in depression and psychosis are probably markers of illness in general.


Subject(s)
Personal Narratives as Topic , Psychotic Disorders/physiopathology , Psychotic Disorders/psychology , Schizophrenia/physiopathology , Schizophrenic Psychology , Verbal Behavior , Adult , Depression/physiopathology , Depression/psychology , Female , Humans , Male , Middle Aged , Young Adult
4.
Cogn Neuropsychiatry ; 21(1): 73-89, 2016.
Article in English | MEDLINE | ID: mdl-26878311

ABSTRACT

We reconsider delusions in terms of a "doxastic shear pin", a mechanism that errs so as to prevent the destruction of the machine (brain) and permit continued function (in an attenuated capacity). Delusions may disable flexible (but energetically expensive) inference. With each recall, delusions may be reinforced further and rendered resistant to contradiction. We aim to respond to deficit accounts of delusions - that delusions are only a problem without any benefit - by considering delusion formation and maintenance in terms of predictive coding. We posit that brains conform to a simple computational principle: to minimize prediction error (the mismatch between prior top-down expectation and current bottom-up input) across hierarchies of brain regions and psychological representation. Recent data suggest that delusions may form in the absence of constraining top-down expectations. Then, once formed, they become new priors that motivate other beliefs, perceptions, and actions by providing strong (sometimes overriding) top-down expectation. We argue that delusions form when the shear-pin breaks, permitting continued engagement with an overwhelming world, and ongoing function in the face of paralyzing difficulty. This crucial role should not be ignored when we treat delusions: we need to consider how a person will function in the world without them..


Subject(s)
Brain/physiopathology , Capgras Syndrome/psychology , Delusions/psychology , Learning , Memory , Association Learning , Capgras Syndrome/physiopathology , Delusions/physiopathology , Humans , Knowledge , Mental Recall , Motivation , Psychological Theory
5.
Br J Psychiatry ; 206(1): 32-8, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24970770

ABSTRACT

BACKGROUND: Language use is often disrupted in patients with schizophrenia; novel computational approaches may provide new insights. AIMS: To test word use patterns as markers of the perceptual, cognitive and social experiences characteristic of schizophrenia. METHOD: Word counting software was applied to first-person accounts of schizophrenia and mood disorder. RESULTS: More third-person plural pronouns ('they') and fewer first-person singular pronouns ('I') were used in schizophrenia than mood disorder accounts. Schizophrenia accounts included fewer words related to the body and ingestion, and more related to religion. Perceptual and causal language were negatively correlated in schizophrenia accounts but positively correlated in mood disorder accounts. CONCLUSIONS: Differences in pronouns suggest decreased self-focus or perhaps even an understanding of self as other in schizophrenia. Differences in how perceptual and causal words are correlated suggest that long-held delusions represent a decreased coupling of explanations with sensory experience over time.


Subject(s)
Anxiety Disorders/psychology , Language , Narration , Schizophrenic Psychology , Female , Humans , Male , Mood Disorders/psychology
6.
Cogn Neuropsychiatry ; 19(6): 540-53, 2014.
Article in English | MEDLINE | ID: mdl-25028078

ABSTRACT

INTRODUCTION: Dreams might represent a window on altered states of consciousness with relevance to psychotic experiences, where reality monitoring is impaired. We examined reality monitoring in healthy, non-psychotic individuals with varying degrees of dream awareness using a task designed to assess confabulatory memory errors - a confusion regarding reality whereby information from the past feels falsely familiar and does not constrain current perception appropriately. Confabulatory errors are common following damage to the ventromedial prefrontal cortex (vmPFC). Ventromedial function has previously been implicated in dreaming and dream awareness. METHODS: In a hospital research setting, physically and mentally healthy individuals with high (n = 18) and low (n = 13) self-reported dream awareness completed a computerised cognitive task that involved reality monitoring based on familiarity across a series of task runs. RESULTS: Signal detection theory analysis revealed a more liberal acceptance bias in those with high dream awareness, consistent with the notion of overlap in the perception of dreams, imagination and reality. CONCLUSIONS: We discuss the implications of these results for models of reality monitoring and psychosis with a particular focus on the role of vmPFC in default-mode brain function, model-based reinforcement learning and the phenomenology of dreaming and waking consciousness.


Subject(s)
Awareness , Consciousness , Delusions/psychology , Dreams/psychology , Memory , Reality Testing , Adult , Female , Healthy Volunteers , Humans , Male , Psychological Tests , Self Report , Signal Detection, Psychological
7.
Neuropsychologia ; 50(14): 3612-20, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23079501

ABSTRACT

Healthy people sometimes report experiences and beliefs that are strikingly similar to the symptoms of psychosis in their bizarreness and the apparent lack of evidence supporting them. An important question is whether this represents merely a superficial resemblance or whether there is a genuine and deep similarity indicating, as some have suggested, a continuum between odd but healthy beliefs and the symptoms of psychotic illness. We sought to shed light on this question by determining whether the neural marker for prediction error - previously shown to be altered in early psychosis--is comparably altered in healthy individuals reporting schizotypal experiences and beliefs. We showed that non-clinical schizotypal experiences were significantly correlated with aberrant frontal and striatal prediction error signal. This correlation related to the distress associated with the beliefs. Given our previous observations that patients with first episode psychosis show altered neural responses to prediction error and that this alteration, in turn, relates to the severity of their delusional ideation, our results provide novel evidence in support of the view that schizotypy relates to psychosis at more than just a superficial descriptive level. However, the picture is a complex one in which the experiences, though associated with altered striatal responding, may provoke distress but may nonetheless be explained away, while an additional alteration in frontal cortical responding may allow the beliefs to become more delusion-like: intrusive and distressing.


Subject(s)
Corpus Striatum/physiopathology , Culture , Delusions/pathology , Delusions/psychology , Frontal Lobe/physiopathology , Corpus Striatum/blood supply , Female , Food Hypersensitivity/diagnosis , Frontal Lobe/blood supply , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Neuropsychological Tests , Oxygen/blood , Predictive Value of Tests , Psychiatric Status Rating Scales
8.
Prog Neurobiol ; 92(3): 345-69, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20558235

ABSTRACT

Delusions are the false and often incorrigible beliefs that can cause severe suffering in mental illness. We cannot yet explain them in terms of underlying neurobiological abnormalities. However, by drawing on recent advances in the biological, computational and psychological processes of reinforcement learning, memory, and perception it may be feasible to account for delusions in terms of cognition and brain function. The account focuses on a particular parameter, prediction error--the mismatch between expectation and experience--that provides a computational mechanism common to cortical hierarchies, fronto-striatal circuits and the amygdala as well as parietal cortices. We suggest that delusions result from aberrations in how brain circuits specify hierarchical predictions, and how they compute and respond to prediction errors. Defects in these fundamental brain mechanisms can vitiate perception, memory, bodily agency and social learning such that individuals with delusions experience an internal and external world that healthy individuals would find difficult to comprehend. The present model attempts to provide a framework through which we can build a mechanistic and translational understanding of these puzzling symptoms.


Subject(s)
Brain/physiology , Brain/physiopathology , Delusions/physiopathology , Delusions/psychology , Models, Neurological , Brain/anatomy & histology , Cognition/physiology , Computer Simulation , Culture , Delusions/etiology , Humans , Learning/physiology , Memory/physiology , Nervous System Diseases/complications , Nervous System Diseases/physiopathology , Neurobiology , Perception/physiology
9.
Psychopharmacology (Berl) ; 206(4): 515-30, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19475401

ABSTRACT

INTRODUCTION: Various experimental manipulations, usually involving drug administration, have been used to produce symptoms of psychosis in healthy volunteers. Different drugs produce both common and distinct symptoms. A challenge is to understand how apparently different manipulations can produce overlapping symptoms. We suggest that current Bayesian formulations of information processing in the brain provide a framework that maps onto neural circuitry and gives us a context within which we can relate the symptoms of psychosis to their underlying causes. This helps us to understand the similarities and differences across the common models of psychosis. MATERIALS AND METHODS: The Bayesian approach emphasises processing of information in terms of both prior expectancies and current inputs. A mismatch between these leads us to update inferences about the world and to generate new predictions for the future. According to this model, what we experience shapes what we learn, and what we learn modifies how we experience things. DISCUSSION: This simple idea gives us a powerful and flexible way of understanding the symptoms of psychosis where perception, learning and inference are deranged. We examine the predictions of the cognitive model in light of what we understand about the neuropharmacology of psychotomimetic drugs and thereby attempt to account for the common and the distinctive effects of NMDA receptor antagonists, serotonergic hallucinogens, cannabinoids and dopamine agonists. CONCLUSION: By acknowledging the importance of perception and perceptual aberration in mediating the positive symptoms of psychosis, the model also provides a useful setting in which to consider an under-researched model of psychosis-sensory deprivation.


Subject(s)
Models, Biological , Psychoses, Substance-Induced/physiopathology , Psychotic Disorders/physiopathology , Animals , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Bayes Theorem , Humans , Psychoses, Substance-Induced/etiology
10.
Mol Psychiatry ; 13(3): 239, 267-76, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17684497

ABSTRACT

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.


Subject(s)
Psychotic Disorders/pathology , Psychotic Disorders/physiopathology , Reward , Substantia Nigra/physiopathology , Ventral Tegmental Area/physiopathology , Adolescent , Adult , Analysis of Variance , Case-Control Studies , Choice Behavior , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Models, Psychological , Neuropsychological Tests , Oxygen/blood , Photic Stimulation/methods , Psychiatric Status Rating Scales , Substantia Nigra/blood supply , Ventral Tegmental Area/blood supply
11.
Brain ; 130(Pt 9): 2387-400, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17690132

ABSTRACT

Delusions are maladaptive beliefs about the world. Based upon experimental evidence that prediction error-a mismatch between expectancy and outcome--drives belief formation, this study examined the possibility that delusions form because of disrupted prediction--error processing. We used fMRI to determine prediction-error-related brain responses in 12 healthy subjects and 12 individuals (7 males) with delusional beliefs. Frontal cortex responses in the patient group were suggestive of disrupted prediction-error processing. Furthermore, across subjects, the extent of disruption was significantly related to an individual's propensity to delusion formation. Our results support a neurobiological theory of delusion formation that implicates aberrant prediction-error signalling, disrupted attentional allocation and associative learning in the formation of delusional beliefs.


Subject(s)
Delusions/etiology , Psychotic Disorders/psychology , Adult , Antipsychotic Agents/pharmacology , Association Learning , Attention , Basal Ganglia/drug effects , Basal Ganglia/physiopathology , Brain Mapping/methods , Female , Frontal Lobe/physiopathology , Humans , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Male , Psychiatric Status Rating Scales , Psychotic Disorders/drug therapy , Psychotic Disorders/physiopathology , Schizophrenic Psychology
12.
J Psychopharmacol ; 21(3): 238-52, 2007 May.
Article in English | MEDLINE | ID: mdl-17591652

ABSTRACT

Recent cognitive neuropsychiatric models of psychosis emphasize the role of attentional disturbances and inappropriate incentive learning in the development of delusions. These models highlight a pre-psychotic period in which the patient experiences perceptual and attentional disruptions. Irrelevant details and numerous associations between stimuli, thoughts and percepts are imbued with inappropriate significance and the attempt to rationalize and account for these bizarre experiences results in the formation of delusions. The present paper discusses delusion formation in terms of basic associative learning processes. Such processes are driven by prediction error signals. Prediction error refers to mismatches between an organism's expectation in a given environment and what actually happens and it is signalled by both dopaminergic and glutamatergic mechanisms. Disruption of these neurobiological systems may underlie delusion formation. We review similarities between acute psychosis and the psychotic state induced by the NMDA receptor antagonist drug ketamine, which impacts upon both dopaminergic and glutamatergic function. We conclude by suggesting that ketamine may provide an appropriate model to investigate the formative stages of symptom evolution in schizophrenia, and thereby provide a window into the earliest and otherwise inaccessible aspects of the disease process.


Subject(s)
Delusions/chemically induced , Delusions/psychology , Excitatory Amino Acid Antagonists , Hallucinogens , Ketamine , Mental Processes/drug effects , Animals , Association Learning/drug effects , Dopamine/physiology , Glutamic Acid/physiology , Humans , Models, Psychological , Synaptic Transmission/physiology
13.
Br J Anaesth ; 98(5): 615-23, 2007 May.
Article in English | MEDLINE | ID: mdl-17389691

ABSTRACT

BACKGROUND: Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models. METHODS: Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml-1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology. RESULTS: For the Domino model, bias, inaccuracy, wobble, and divergence were - 2.7%, 33.9%, 24.2%, and 0.1463% h-1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias. CONCLUSIONS: Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration.


Subject(s)
Anesthetics, Dissociative/administration & dosage , Ketamine/administration & dosage , Models, Biological , Adolescent , Adult , Anesthetics, Dissociative/blood , Cognition/drug effects , Drug Administration Schedule , Drug Delivery Systems , Female , Humans , Infusions, Intravenous , Ketamine/blood , Male , Middle Aged , Neuropsychological Tests , Predictive Value of Tests , Prospective Studies
14.
Br J Psychiatry ; 189: 173-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16880489

ABSTRACT

BACKGROUND: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically. AIM: To examine the effects of ketamine in healthy people using a structured psychiatric interview. METHOD: Ketamine (200 ng/ml) or placebo was administered by continuous infusion to 15 healthy volunteers. Symptoms were rated using the Present State Examination, the Thought, Language and Communication Scale and the Scale for Assessment of Negative Symptoms. RESULTS: Ketamine induced a range of perceptual distortions, but not hallucinations. Referential ideas were seen in nearly half the sample. There were only mild and infrequent ratings on the thought disorder scale. Affective flattening and alogia were seen in some volunteers. CONCLUSIONS: Ketamine does not reproduce the full picture of schizophrenia. The main point of similarity concerns referential thinking. Phenomena resembling negative symptoms are also seen, but the distinction of these from the drug's sedative effects requires further elucidation.


Subject(s)
Excitatory Amino Acid Antagonists/adverse effects , Ketamine/adverse effects , Psychoses, Substance-Induced/etiology , Adult , Brief Psychiatric Rating Scale , Central Nervous System/drug effects , Cognition Disorders/chemically induced , Delusions/chemically induced , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/blood , Female , Hallucinations/chemically induced , Humans , Infusions, Parenteral , Interview, Psychological , Ketamine/administration & dosage , Ketamine/blood , Male , Middle Aged , Mood Disorders/chemically induced , Perceptual Disorders/complications
15.
Cereb Cortex ; 15(7): 1002-15, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15537672

ABSTRACT

Under certain circumstances, implicit, automatic learning may be attenuated by explicit memory processes. We explored the brain basis of this phenomenon in a functional magnetic resonance imaging (fMRI) study of motor sequence learning. Using a factorial design that crossed subjective intention to learn (explicit versus implicit) with sequence difficulty (a standard versus a more complex alternating sequence), we show that explicit attempts to learn the difficult sequence produce a failure of implicit learning and, in a follow-up behavioural experiment, that this failure represents a suppression of learning itself rather than of the expression of learning. This suppression is associated with sustained right frontal activation and attenuation of learning-related changes in the medial temporal lobe and the thalamus. Furthermore, this condition is characterized by a reversal of the fronto-thalamic connectivity observed with unimpaired implicit learning. The findings demonstrate a neural basis for a well-known behavioural effect: the deleterious impact of an explicit search upon implicit learning.


Subject(s)
Brain/physiology , Magnetic Resonance Imaging , Memory/physiology , Neural Inhibition/physiology , Serial Learning/physiology , Adult , Brain/cytology , Female , Frontal Lobe/cytology , Frontal Lobe/physiology , Humans , Male , Neural Pathways , Temporal Lobe/cytology , Temporal Lobe/physiology , Thalamus/cytology , Thalamus/physiology
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