Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine ...dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain-control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis.
•Auditory hallucinations are linked to a perceptual bias toward uncertain expectations•Elevated striatal dopamine function relates to the same pattern of perceptual bias•Volume of dorsal anterior cingulate relates to the same pattern of perceptual bias
Cassidy et al. induced auditory illusions to test a dopamine-dependent cognitive mechanism for hallucinations. Unmedicated schizophrenia patients with auditory hallucinations perceived tone durations in a way similar to what was expected, even when expectations were imprecise, and this perceptual bias related to excess dopamine function.
The clinical high-risk state in psychosis is most often characterized by subthreshold psychotic symptoms (STPS) and represents a target for psychosis prevention. However, evidence suggests that ...between 30% and 50% of patients with a first episode of psychosis (FEP) report no prior history of STPS, indicating that not all patients with FEP experience a previous clinical high-risk phase. As with other early characteristics of illness onset, this diversity in the early course of symptoms may offer prognostic value for subsequent clinical trajectories.
To determine whether a history of pre-onset STPS is associated with differential 1-year treatment outcomes in an early intervention service for FEP.
Data on 195 patients 15 to 35 years of age who were recruited between January 17, 2003, and October 17, 2013, were collected from a catchment-based specialized early intervention service for FEP. Patients who reported experiencing at least 1 STPS prior to the onset of FEP were identified as STPS present (STPSp; n = 135); those who reported no such history were identified as STPS absent (STPSa; n = 60). Statistical analysis was conducted from December 15, 2016, to February 15, 2018.
Summary scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia, Hamilton Anxiety Rating Scale, Global Assessment of Functioning scores, and Social and Occupational Functioning Assessment Scale scores at baseline and after 1 year of treatment were analyzed to evaluate 1-year outcomes.
Individuals in the STPSp group (39 female and 96 male participants; mean SD age, 23.4 4.2 years) and the STPSa group (20 female and 40 male participants; mean SD age, 23.9 5.1 years) did not differ in symptom severity or functioning at baseline. Although both groups improved by 1 year of treatment, mixed analyses of covariance (controlling for duration of untreated psychosis) revealed group-by-time interactions for scores on the Scale for the Assessment of Negative Symptoms (F1,192 = 6.17; P = .01), the Global Assessment of Functioning (F1,188 = 7.54; P = .006), and the Social and Occupational Functioning Assessment Scale (F1,192 = 3.79; P = .05). Mixed analyses of covariance also revealed a group effect for scores on the Scale for the Assessment of Positive Symptoms (F1,192 = 5.31; P = .02). After controlling for multiple comparisons, all significant results indicate poorer 1-year outcomes for patients with STPSp compared with patients with STPSa.
A history of pre-onset STPS consistent with a prior clinical high-risk state is associated with poorer outcomes in psychotic symptoms and global functioning for patients after 1 year of treatment for FEP. The presence or absence of pre-onset STPS therefore has prognostic value for treatment outcomes, even during a later stage of psychotic illness.
Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown ...agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and
Craclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg
dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BP
) and derived percent reduction from baseline (ΔBP
) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BP
to baseline differed between SZ and HCs, we implemented a linear model with ΔBP
as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBP
(F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BP
to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.
Uncensored Exchange of Scientific Results Atlas, Ronald; Campbell, Philip; Cozzarelli, Nicholas R ...
Proceedings of the National Academy of Sciences - PNAS,
02/2003, Volume:
100, Issue:
4
Journal Article
Statement on scientific publication and security Atlas, Ronald; Campbell, Philip; Cozzarelli, Nicholas R ...
Science (American Association for the Advancement of Science),
2003-Feb-21, Volume:
299, Issue:
5610
Journal Article
Peer reviewed
In a one-day workshop at the Academy of Washington on Jan 9, 2003, an open forum was held to discuss the possibility that new information published in research journals might give aid to those with ...malevolent ends. A day later, a group of journal editors, augmented by scientist-authors, government officials and others, held a separate meeting designed to explore possible approaches to this issue. Some outcomes from the preliminary discussion are presented.
PDF
