Modelling perception as a hierarchical competition 9 Serotonin and acetylcholine: neurologically plausible bottom-up and top-down weighting agents This model implies that neural agents exist which modulate the relative contribution of top-down and bottom-up processes. Given that this model predicts that weighting schemes affect veridical and hallucinatory perception as well as mental imagery, agents that modulate these processes might also be apt candidate weighting agents in our current model. Serotonin may be one such agent that modulates the contribution of bottom-up information during visual percep-tion. Classic hallucinogens act on the serotonergic system via 5-hydroxytryptamine 2A (5HT2A) receptors ( Nichols 2016), and cortical serotonin levels are dependent on plasma levels of tryptophan, serotonin's precursor, which readily crosses the blood-brain barrier (Fernstrom and Wurtman 1971 ). Plasma tryp-tophan increases over the course of the day, peaking in the late evening ( Rao et al. 1994), approximately corresponding to the most common time of hallucination onset for individuals with Charles Bonnet syndrome, peduncular hallucinosis, and Parkin-son's disease, including for those without any ability to perceive light ( Manford and Andermann 1998 ). Furthermore, 5HT2A recep-tor expression in the ventral visual pathway of Parkinson's disease hallucinators is elevated compared to non-hallucinators ( Bal-langer et al. 2010 ; Huot et al. 2010 ), while inverse agonists for this receptor are used to treat Parkinson's disease hallucinations (Yasue et al. 2016). Outside of hallucinatory states, serotonin administered in the primary visual cortex of awake macaques acts as a gain modulator, dampening cell responses to external sen-sory input without affecting stimulus tuning or selectivity profiles (Seillier et al. 2017). In mice, this dampening in V1 was mediated by a 5HT2A receptor agonist (Michaiel et al. 2019). Additionally, acetylcholine may modulate the contribution of top-down information during visual experience. The ratio of acetylcholine to serotonin is a factor in hallucination aetiology (Manford and Andermann 1998), and both serotonin and acetyl-choline target Layer 5 cortical pyramidal neurons, cells which have been proposed as essential for manifesting conscious sen-sory perception (Aru et al. 2019 ). High concentrations of acetyl-choline can transition the activity of Layer 5 cortical pyrami-dal neurons from being driven by feedforward inputs to feed-back inputs, which may mediate the hallucinatory experience of dreaming (Aru et al. 2020 ). The concentration of cortical acetyl-choline peaks during rapid eye movement sleep, where dreaming is most likely, higher than during wakefulness and higher still than during non-rapid eye movement sleep where consciousness is greatly impaired (Lee et al. 2005). Hence, cortical acetylcholine concentrations may modulate feedback connectivity in sensory cortices. Given their actions in the visual system, serotonin and acetyl-choline levels could be plausible factors accounting for contextual and interindividual differences in the perceptual experience of mental imagery. Accordingly, they could also be considered as fac-tors which modulate interlayer weightings within our proposed model. However, ascertaining the role of such neurotransmit-ters in mental imagery research is challenged by a reliance on human models for self-report, indistinct metrics and constructs (e. g. vividness ratings), and the restricted access of psychoactive serotonergic drugs. Ultimately, there are many mechanisms by which our model can facilitate hallucinations and such mecha-nisms may work in tandem. Note that in all cases, our model does not explain how the initial internally generated source stimulus might be produced, only how it may be represented, regard-less of whether it was generated as part of a voluntary thought, involuntary hallucination, or otherwise. Mental imagery as a dynamic process So far, our predictions have been based on simulations where imagery, once generated, continues to be generated indefinitely and without interruption. Under these conditions, internally gen-erated content can continue to spread downwards until it reaches an equilibrium point and can spread no further. Yet, if imagery is interrupted or generated intermittently, it may never be gen-erated for a period long enough for it to spread to its maximum possible extent, even if the balance of top-down and bottom-up processes favours a very low equilibrium point (i. e. highly sensory mental imagery). Analogously, even though the maximum possi-ble speed of a sports car may be faster than that of a van, the sports car will be outpaced if the van driver keeps the pedal floored while the sports car driver only taps the pedal on and off. If mental image content can be generated continuously, or supported by a stream of simulated sensory information at lower levels, then the chances of that content spreading to its maximum possible extent are increased. Visual versus auditory mental imagery Although we have focused on visual mental imagery, men-tal imagery can occur in other sensory modalities, presumably through similar generative feedback. A complete account of men-tal imagery should be able to predict and explain modality-specific differences in imagined experience. Auditory hallucinations are roughly twice as common as visual hallucinations in schizophre-nia and bipolar disorder (Waters et al. 2014), although how experi-ences differ between modalities specifically for mental imagery is not well understood. Comparisons generally rely on mental image vividness ratings (e. g. Betts 1910 ; Sheehan 1967 ; Switras 1978; Gissurarson 1992 ; Schifferstein 2009 ; Andrade et al., 2014; Talamini et al. 2022 ). Yet, as such rating systems are ambigu-ously defined and difficult to meaningfully interpret ( Richardson 1988), findings have been understandably mixed. Here, we make predictions about how the quality of mental imagery may differ between visual and auditory mental imagery, perhaps the two most-studied imagery modalities, based on the differences in the brain's ability to synthesize sensory information in each modality. Unlike with visual stimuli, our bodies are readily capable of producing their own auditory stimuli using speech. Self-initiated movements, including the act of speech, produce signals (e. g. efference copies) that carry temporally precise predictions of the sensory consequences of such movements (Curio et al. 2000 ). Sen-sory predictions related to motor movements have been suggested to aid mental imagery when they are produced in the absence of real movements (Scott 2013 ; Whitford et al. 2017; Gelding et al. 2019; Jack et al. 2019; Pruitt et al. 2019 ). This could occur by supplying imagination with the sensory content needed to gen-erate a mental image or by supporting existing mental imagery with a stream of sensory predictions linked to real or simulated movements. As discussed previously, anchoring mental images to continuous sensory information should improve the quality of mental imagery under our model. While visual mental images could be supported by sensory pre-dictions from real or simulated eye movements, eye movements generally contain information about where imagined content is, was, or will be (e. g. Fourtassi et al. 2017). However, they are far less informative about what the content actually is that is being Downloaded from https://academic. oup. com/nc/article/2023/1/niad018/7248966 by guest on 25 August 2024 