Oportunidad de desarrollo

Normal object perception is thought to be the result of the complex interplay between external ‘bottom-up’ visual input, and internal ‘top-down’ representations of objects and scenes, termed ‘proto-objects’, formed as a result of visual experience, and deployed on the basis of expectations (Wolfe et al., 2003). Competition is thought to exist between both bottom-up visual input and top-down expectations to bias

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dysfunctional sensory input processing biases toward top-down expectations and contributes to the selection of incorrect proto-objects (Collerton et al., 2005b). Crucially, scene perception remains intact, so the perceived proto-object is

congruous with the observed scene but incorrect. Under normal conditions, attention affixes proto-objects into the observed visual scene, and this process is also thought to be perturbed in the PAD model (Lu and Dosher, 1998). Therefore, under the PAD model, impairments in object perception contribute to incorrect proto-object selection, and attentional dysfunction fixes incorrect, though contextually congruous objects, into the subjective visual scene, which are perceived as visual hallucinations

(Collerton et al., 2005a). The authors of the PAD hypothesis have tested this model by assessing perception and attention in patients with a dementia diagnosis and controls (Makin et al., 2013). They found attention, but not visual acuity, was significantly deficient in dementia cases with visual hallucinations, offering some support for the PAD hypothesis. Lower scores of sustained attention in hallucinating PD patients (Meppelink et al., 2008) and the disappearance of visual hallucinations following focused attention (Diederich et al., 2003) further indicate a role for attention in the aetiology of visual hallucinations in Lewy body disease.

The PAD hypothesis and subsequent experimental work have implicated

dysfunctional attentional processes in the aetiology of complex visual hallucinations (Collerton et al., 2005b; Meppelink et al., 2008; Makin et al., 2013). Therefore, dysfunction or degeneration of regions implicated in visual attentional mechanisms may contribute to the manifestation of visual hallucinations in DLB. The LGN receives widespread inputs from regions that modulate visual activity, such as the superior colliculus and thalamic reticular nucleus (Jones, 2012). As it is an early relay structure for afferent visual processing, the LGN is ideally placed to modulate visual input in response to attentional and behavioural demands. Increased activity has been reported in the LGN as a consequence of focused attention, indicating that attention modulates activity in the LGN (O'Connor et al., 2002). However, attention- mediated activity changes in the LGN are likely the result of modulatory feedback from the primary visual cortex to the reticular thalamic nucleus, which gates LGN activity patterns (Montero, 2000; Jones, 2012).

The pulvinar is thought to have an important role in visual attentional mechanisms (Jones, 2012; Benarroch, 2015) and its widespread cortical connections are thought

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to underlie its putative function in modulating cortico-cortical activity based on attentional demands (Saalmann et al., 2012). Lesions of the pulvinar lead to deficits in filtering distracting visual stimuli (Fischer and Whitney, 2012) and in attending to specific features of an observed stimulus (Ward et al., 2002). Taken together, this indicates a functional role for the pulvinar in visual attention.

The Sprague effect, where spatial neglect occurs as a result of lesions to the occipital or parietal lobe, is recovered following superior colliculus lesioning,

suggesting its contribution to visual attention (Sprague, 1966; Weddell, 2004). Like the LGN, the superior colliculus shows increased activity when the observer is attending to a visual stimulus, albeit with substantially higher attention-mediated activity than the LGN (Schneider and Kastner, 2009). Stimulation of collicular regions bias eye and head/neck movements toward spatial locations corresponding to the retinotopic area stimulated, indicating a role in target selection (Corneil et al., 2002; Gandhi and Katnani, 2011). Microstimulation of the superior colliculus can also spatially focus attention without eye movements toward the area of attention, a phenomenon known as covert attention (Muller et al., 2005).

Perception and attentional deficits in DLB are thought to be the result of cholinergic dysfunction (Collerton et al., 2005b). Post-mortem studies have demonstrated cholinergic deficits in DLB, often exceeding those found in AD (Perry et al., 1990a; Perry et al., 1994; Tiraboschi et al., 2002), and these have been suggested to contribute a vulnerability to visual hallucinations (Perry and Perry, 1995). The major cholinergic nuclei, such as the nucleus basalis of Meynert (Lippa et al., 1999; Kim et

al., 2011; Grothe et al., 2014) and pedunculopontine nucleus (Schmeichel et al.,

2008; Hepp et al., 2013), typically manifest Lewy body pathology in DLB. A

physiological study that measured activity as an analogue of cholinergic activity has demonstrated changes in DLB which are commensurate with visual hallucination frequency and severity (Marra et al., 2012). An imaging study targeting cholinergic receptors in vivo has also suggested alterations in cholinergic uptake associated with visual hallucinations (O'Brien et al., 2008). A relationship between cholinergic

dysfunction and visual hallucinations is further implied by reports of

29 1.6.3 ‘Blind’ to blindsight

Blindsight is the ability of blind individuals to utilise facets of observed visual scenes without conscious awareness of perception (Barbur, 2004). Specifically, individuals with blindsight often accurately locate or identify presented stimuli within their peripheral visual field, react to moving stimuli and perform eye movements to follow and move between presented objects, despite an inability to consciously perceive them (Stoerig and Cowey, 1997). More recent work indicates that emotion-laden images may be perceived in an analogous manner termed ‘affective blindsight’ (Tamietto and de Gelder, 2010). PD patients often inappropriately guess objects in their peripheral visual fields, have difficulty perceiving motion, exhibit eye movement deficiencies and have impairments in recognising emotional facial stimuli, suggesting they have the converse of blindsight (Diederich et al., 2014). The ‘blind’ to blindsight syndrome is thought to contribute to the occurrence of presence and passage hallucinations, simple hallucinations where an object or movement is incorrectly perceived in the peripheral visual field. Deficient blindsight pathways in Lewy body disease may also force reliance upon the longer-latency primary visual pathway for information normally carried along the faster secondary visual pathways (Diederich

et al., 2014). It is possible that slowed transfer of supportive visual information could

lead to an over-reliance upon top-down processing in visual perception, particularly in circumstances of changing visual conditions, and bias the individual towards expected, rather than experienced, visual stimuli. This could contribute toward visual hallucination if top-down processes are also dysfunctional.

The hypothesis that Lewy body disorder patients are ‘blind’ to blindsight suggests brain structures with functional roles in motion perception, eye movements and perception of emotional stimuli will be pathologically dysfunctional. Four brain structures, the LGN, pulvinar, superior colliculus and amygdala, have been directly implicated in these functions and in blindsight pathways hypothesised to be

dysfunctional in Lewy body disease (Diederich et al., 2014). Koniocellular neurons of the LGN directly innervate the cortical motion perception area, V5/MT, in a pathway thought to contribute to the blindsight phenomenon (Sincich et al., 2004; Schmid et

al., 2010). However, magnocellular and parvocellular neurons of the LGN, which are

not part of putative blindsight pathways and primarily innervate the primary visual cortex, also show sensitivity to motion (Lee et al., 1979).

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The SGS of the superior colliculus is thought to have a role in motion perception as it contains motion sensitive neurons (Inayat et al., 2015). Additionally, the SGS

receives direct retinal input and projects to the motion area V5/MT through the inferior aspect of the pulvinar, in a pathway with a putative role in the non-conscious perception of motion (Lanyon et al., 2009) and may, therefore, contribute to motion perception deficits in Lewy body disorders (Diederich et al., 2014). The SGI of the superior colliculus also has an important role in selecting the targets of upcoming saccadic and pursuit eye movements (Glimcher and Sparks, 1992; Krauzlis and Dill, 2002), which are deficient in Lewy body disorders (Mosimann et al., 2005; Diederich

et al., 2014). In particular, DLB patients have increased saccadic latency and a

tendency to perform saccades that fall short of their target (Mosimann et al., 2005), an identical pattern of deficits to that observed when the SGI of non-human primates is chemically inactivated (Aizawa and Wurtz, 1998).

In addition to the role of the pulvinar in relaying motion information from the superior colliculus to V5/MT, the medial aspect of the pulvinar has substantial connectivity with the amygdala (Romanski et al., 1997), in which high levels of Lewy body

pathology have been associated with visual hallucinations (Harding et al., 2002). PD patients show impaired perception of fear in observed faces (Sprengelmeyer et al., 2003), and lesions specifically affecting the medial pulvinar lead to impaired fear perception, particularly in observed faces (Ward et al., 2007), indicating the medial pulvinar may contribute to affective blindsight (Diederich et al., 2014).