Auditory hallucinations are among the most distressing aspects of psychotic illness, and
between 10 and 30% of people with hallucinations do not respond to antipsychotic
medications. The authors have used computational modeling of behavior to link brain
activity to development of auditory hallucinations in the hope of guiding new treatment
development. The proposed studies take the first step toward individualized treatment
approaches to hallucinations by attempting causal, pharmacological manipulation of
relevant model parameters underlying these phenomena.

Toward a Computationally-Informed, Personalized Treatment for Hallucinations

Hallucinations, Auditory

Psychosis

Auditory verbal hallucinations (AVH) are present throughout the course of psychotic
illness and are among its most distressing symptoms. The presence of hallucinations alone
increases risk of suicide in patients with psychosis. While antipsychotic medications
often succeed in ameliorating auditory hallucinations, 10-30% of those with
hallucinations exhibit little to no response to these treatments. Understanding how the
processes underlying auditory perception might go awry to produce auditory hallucinations
is a critical next step in the development of new treatments that are more soundly based
upon systems neuroscience and brain pathophysiology.

Perceptual systems do not rely entirely upon information coming from sensory organs like
the retina and the cochlea. Rather, they blend this input with perceptual beliefs about
the sensory environment in order to produce an internal model of that environment. The
authors and others have proposed that hallucinations may be seen as an over-weighting of
these perceptual beliefs when combined with sensory evidence during perceptual inference.
In this work, the authors take advantage of a long history of sensory conditioning
research to elicit hallucinatory experiences via traditional learning mechanisms:
subjects are exposed to repeated pairings of visual and auditory stimuli and subsequently
perceive the presence of the auditory stimulus when only the visual is present. The
authors applied this Conditioned Hallucinations paradigm to four groups of subjects who
varied orthogonally in having or not having hallucinations and psychosis. The authors
found that conditioned hallucinations readily occur in all subjects but with markedly
increased frequency in those who hallucinate compared to those who do not. The authors
then employed a computational approach that formally models perception as a combination
of prior knowledge and sensory input: the Hierarchical Gaussian Filter (HGF). Results
indicate that the weight prior knowledge exerts during perception is significantly higher
in those with hallucinations, and is related to prior-related functional activity
specific brain regions like the anterior insula. This 'prior weighting' alteration may
represent a novel, personalized, and computationally-informed target for the treatment of
hallucinations.

Mathematically, prior weighting is the ratio of the precision of prior knowledge to the
precision of incoming sensory evidence exhibited by an individual during perception.
Therefore, it may be normalized by either decreasing the precision of prior knowledge or
increasing the precision of incoming sensory evidence. The precision of sensory evidence
appears to depend critically upon cholinergic signaling: acetylcholine increases auditory
discrimination abilities and biases perceptual inference toward sensory data. Antagonism
at central cholinergic receptors decreases sensory sensitivity and decreases reliance on
incoming sensory evidence during perceptual inference. Consistent with this, scopolamine,
a safe and reversible antagonist at the M1 cholinergic receptor used routinely for its
anti-emetic effects, can both cause spontaneous hallucinations and enhance conditioned
hallucinations. By contrast, increased cholinergic signaling ameliorates psychotic
symptoms in schizophrenia and Alzheimer's Disease. Rivastigmine, a reversible,
centrally-acting cholinesterase inhibitor, has been used study the cholinergic system and
has been found to ameliorate hallucinations in some patients with schizophrenia.

The authors plan to characterize the effects of cholinergic agents on the perceptual,
computational, physiological, and clinical signatures of hallucinations in healthy
participants and individuals with psychosis via the following aims:

Aim 1: Characterize the effects of cholinergic antagonism on the behavioral,
computational, and neural signatures of conditioned hallucinations in healthy subjects.
Hypotheses: 1) Non-hallucinating healthy subjects will show increases in prior weighting
and conditioned hallucinations with scopolamine vs. saline. 2) Scopolamine-related
changes in prior weighting will be accompanied by increased prior-related activity in
anterior insula on functional MRI (fMRI).

Aim 2: Determine the effect of cholinergic potentiation on the behavioral, computational,
and neural signatures of conditioned hallucinations in subjects with psychosis and
hallucinations. Hypotheses: 1) Subjects with hallucinations and high prior weighting will
show decreases in prior weighting and conditioned hallucinations with rivastigmine patch
vs placebo patch. 2) Rivastigmine-related changes in prior weighting will be accompanied
by lower prior-related functional activity in anterior insula. 3) Subjects with
hallucinations and lower prior weighting will show none of these physostigmine-related
changes.

In proposing these aims, the authors apply a formalized, theoretical understanding of
perceptual processing to probe the interplay between perceptual, computational,
circuit-level, and neurotransmitter-level dysfunction seen in hallucinations. This
approach also has the potential for an immediate clinical impact: it is the first attempt
to leverage the powerful tools of computational psychiatry to identify distinct patient
subgroups likely to respond to emerging cholinergically-mediated treatments for
hallucinations.

Rivastigmine Transdermal System

Scopolamine

Placebo Patch

Participants will perform the Conditioned Hallucinations task while in the scanner; the
authors hypothesize that number of conditioned hallucinations exhibited during the task
will be higher under placebo than physostigmine, but only in those who have high prior
weighting on baseline assessment.

Behavioral responses will be used to fit a parameter of the Hierarchical Gaussian Filter
model corresponding to the ratio of precision of priors to precision of incoming sensory
evidence.

Behavioral responses will be used to fit belief trajectories across the course of the
experiment, and whole-brain analyses will measure correlation of brain activity with
these computed trajectories.

Participants who have a psychosis spectrum diagnosis and frequent auditory hallucinations
will be given Rivastigmine capsule versus placebo capsule.

Healthy controls will be given scopolamine patches versus placebo patch.

Toward a Computationally-Informed, Personalized Treatment for Hallucinations

About this trial

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Placebo

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