Extensive damage to the visual cortex on one side of the brain produces blindness in the opposite hemifield (hemianopia) despite the sparing of other visual centers far from the site of the physical insult (Sand et al., 2013; Goodwin, 2014). Of special note is the superior colliculus (SC), a midbrain structure that plays a major role in detecting, localizing, and orienting to visual targets. Its multisensory neurons allow it to use non-visual cues to facilitate this process (Stein and Meredith, 1993), and its location in the midbrain ensures that it is not directly damaged by a hemianopia-inducing cortical insult. Yet, as shown in the cat model of hemianopia, the loss of visual responses in the multisensory layers of the SC and the total absence of visual detection and orientation responses to contralateral visual stimuli following lesions of visual cortex reveal that it too is compromised, presumably via secondary excitotoxic injuries that may alter other input structures such as the basal ganglia (Jiang et al., 2009, 2015). Interestingly, the dysfunction of SC appeared to be limited to its visual role. Its other sensory representations and sensorimotor roles remained intact: SC-mediated auditory and tactile detection and orientation responses were readily elicited (see also Sprague and Meikle, 1965).
Previously it was shown that hemianopia could be reversed using a non-invasive multisensory training paradigm (Jiang et al., 2015). The procedure consisted of presenting cross-modal combinations of spatiotemporally congruent auditory-visual cues in the blind hemifield of alert animals engaged in a sensory localization task. Because the animals were not deafened by the cortical lesion, they readily responded to the auditory-visual stimulus complex. After only a few weeks of daily multisensory training sessions, a striking change occurred: not only could the animals now detect and localize a visual stimulus throughout the previously blind hemifield, but they could also discriminate elementary visual patterns there. Visual responses that had been lost in the multisensory layers of the ipsilesional SC also returned, and cortico-SC circuits normally engaged in multisensory integration (i.e., projections from the anterior ectosylvian sulcus, AES) were found to be crucial for the recovery. The recovery could not be induced by training with visual or auditory cues alone. In an important series of studies in human patients, Làdavas and colleagues (Bolognini et al., 2005; Leo et al., 2008; Passamonti et al., 2009; Dundon et al., 2015a,b) used a similar training paradigm and also met with success in evoking contralesional visual responses.
It is commonly believed that the success of this rehabilitative paradigm is a retraining of the visuomotor targeting behavior itself (see, review in Dundon et al., 2015a). In this case, the key factor would be the orienting action (initially elicited by the auditory stimulus) in the presence of the visual stimulus. Also, if true, it is reasonable to hypothesize that the effectiveness of this paradigm would be facilitated by other factors such as motivation, attention, arousal, and reinforcement, as these are commonly believed to enhance most neuro-rehabilitative therapies. An alternative explanation, however, is that the paradigm operates via the brain’s inherent mechanisms for multisensory plasticity, which operate independent of these factors and can be engaged under anesthesia (Yu et al., 2013). In this case, the requirement would only be repeated, reliable exposure to the visual-auditory stimulus complex in the blinded hemifield. The present study examined this possibility directly.
Materials and Methods
Adult mongrel cats (four male, three female) were obtained from a USDA-licensed commercial animal breeding facility (Liberty Labs, Waverly, NY, USA). The experimental procedures used were in compliance with the National Institutes of Health “Guide for the Care and Use of Laboratory Animals” (8th edition, NRC 2011) and approved by the Institutional Animal Care and Use Committee at Wake Forest School of Medicine. Each animal was first screened to ensure that it was tractable and responded to visual and auditory stimuli in both hemifields. All efforts were made to minimize the number of animals used.
Visual Detection and Orientation Testing
Visual orientation capabilities were quantitatively evaluated in a semicircular perimetry arena using previously described methods (see Jiang et al., 2015, see also Figure 1A). Animals were maintained at 80%–85% of body weight and obtained most of their daily food intake during, or immediately after, each behavioral session. Each animal was first trained to fixate directly ahead at a food reward held in forceps by one experimenter and protruded through a hole in the front wall of the apparatus 58 cm ahead at the 0° fixation point. Trial initiation was always contingent upon the animal establishing fixation. Once released by the animal handler (a second experimenter), the animal was required to move directly ahead to obtain the food reward. It was then trained to respond to the test stimulus (a white ping-pong ball at the end of a stick) presented at any 15° interval from 105° left to 105° right. This required little training as animals responded to the stimulus almost reflexively. Stimuli were presented manually and introduced suddenly from behind a black curtain while the animal was fixating. Additionally, on some trials, the ball remained hidden behind the opaque curtain and was tapped on the side of the apparatus to produce an auditory stimulus. If the animal oriented to and approached any test stimulus it was rewarded there, but could also move directly ahead to obtain a similar reward at the fixation point. The animal handler did not know the location of the upcoming test stimulus. This was determined by the experimenter holding the food reward, who also ensured that the trial did not begin if the animal had broken fixation. The verbal command “Go” triggered the release of the animal. “Catch trials” in which no stimulus was presented were interleaved with test trials at different locations to encourage the animal to minimize breaks in fixation, scanning movements, and “false” responses. Generally, in a given session, each of the 15° locations was tested at least 4–5 times. With few exceptions, the total number of trials/location was at least 100. The training criterion was an average of 95% correct responses. All animals reached criterion readily, had normal visual fields, and their weekly weight records revealed stable weight profiles.