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1Centre for Brain and Mind, Department of Physiology and Pharmacology and Department of Psychology, University of Western Ontario, London, Ontario, Canada; and 2Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Submitted 25 July 2006; accepted in final form 22 November 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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showed that removal of a minimum of the superficial and intermediate layers of the contralesional superior colliculus could reverse the impact of the visual cortex ablation on visual orienting and went one step further, to show that it was not necessary to ablate the contralesional superior colliculus, but merely sever the intertectal commissure (Sprague 1966). The restoration of visual orienting after large visual cortical ablations is a phenomenon that has become known as the "Sprague Effect." This restoration was repeatedly demonstrated in numerous studies of the cat (Ciaramitaro et al. 1997; Lomber et al. 2002; Rosenquist et al. 1996; Sherman 1977; Wallace et al. 1989, 1990) and a recent human case also suggests that the effect can be identified in human subjects (Weddell 2004).
In the auditory system, although large unilateral lesions involving primary auditory and much of the remaining acoustically responsive cortex (Fig. 1) do not result in deafness in the contralesional hemifield, because each hemisphere receives input from both ears, they do result in profound sound localization deficits confined to the contralesional hemifield (Casseday and Diamond 1977; Cranford et al. 1971; Neff 1968; Neff et al. 1956; Jenkins and Masterton 1982; Strominger 1969; Thompson and Welker 1963; Whitfield et al. 1972). Although large ablations of acoustically responsive cortex produce a deficit in the contralesional hemifield, much smaller deactivations in auditory cortex also produce contralateral impairments. Specific removal or deactivation of primary auditory cortex (AI), the posterior auditory field (PAF), or the auditory field of the anterior ectosylvian sulcus (AES) produces sound localization deficits in the contralateral hemifield (Casseday and Diamond 1977; Jenkins and Masterton 1982; Jenkins and Merzenich 1984; Malhotra et al. 2004; Malhotra and Lomber 2006; Strominger 1969; Whitfield et al. 1972). However, the effects of the large lesions appear to be more profound than the smaller individual deactivations.
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; Hess et al. 1946; Lomber et al. 2001; Sprague and Meikle 1965; Tunkl 1980). The SC is a laminated structure and can be divided into superficial and deeper layers (Kanaseki and Sprague 1974), with the superficial layers receiving input almost exclusively from visual structures (Graybiel 1975; Harting and Guillery 1976; Harting et al. 1992), whereas deeper layers receive afferents from visual, auditory, and somatosensory cortices (Clemo and Stein 1984; Harting et al. 1992; Meredith and Clemo 1989; Tortelly et al. 1980). Accordingly, superficial layer neurons are exclusively visual, whereas deeper neurons respond to visual, acoustic, and somatosensory stimuli and many respond to more than one modality (Meredith and Stein 1986; Peck 1990; Stein et al. 1976; Wallace et al. 1993). Visual and auditory space and the body surface are mapped across the populations of neurons and the maps are in register across modalities and layers (reviewed by Stein 1984). Visual space can be mapped in both the superficial (Feldon et al. 1970) and deep (Meredith and Stein 1990) layers of the SC, whereas auditory space is mapped only in the deeper layers (Middlebrooks and Knudsen 1984; Palmer and King 1982). Therefore it was not surprising that deactivation of the SC must include both the superficial and deeper layers (SGI) to produce a deficit in accurate orienting to targets presented in the contralateral field (Lomber et al. 2001). In contrast, deactivation of only the superficial layers (SGS) is required to produce a deficit in orienting to visual targets presented in the contracooled field (Lomber et al. 2001). This view for a bipartite separation of function among the superficial and deep collicular layers has been bolstered by numerous anatomical, physiological, and behavioral studies (e.g., Casagrande and Diamond 1974; Casagrande et al. 1972; Edwards 1980; Harting et al. 1992; Stein and Meredith 1991, 1993). Overall, because ablation of all visually or acoustically responsive cortex results in modality-specific deficits in the contralesional hemifield and deactivation of the contralesional SC can reverse the visual impairment, we asked the question: Is the restoration of orienting responses into an impaired hemifield after deactivation of the superior colliculus unique to the visual system? We hypothesized that deactivation of the superior colliculus contralesional to a large ablation of auditory cortex would restore acoustic orienting responses into the impaired hemifield. To test this hypothesis we trained cats to orient to an acoustic stimulus and examined their behavior during both individual and simultaneous deactivation of: 1) acoustically responsive cortex in one hemisphere and 2) the contralesional superior colliculus. The auditory cortex ablations resulted in profound deficits in orienting to acoustic stimuli presented at any position in the contralesional hemifield. The additional deactivation of the superficial and intermediate layers of the contralesional SC restored acoustic orienting responses into the right hemifield. These results confirmed our hypothesis that the "Sprague Effect" is not unique to the visual system and deactivation of the contralesional SC can restore either visual or acoustic orienting responses into an impaired hemifield after cortical damage.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Three mature (>6 mo old) domestic cats were obtained from a commercial laboratory animal breeding facility (Liberty Labs, Waverly, NY) and housed as a colony with unlimited access to water. Food intake was controlled and limited to the behavioral training/testing sessions and to 1 h at the conclusion of each day, when the animals had unlimited access to dry cat food. All procedures were conducted in accordance with the Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals (1993) and National Research Council's Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) and with the approval of the Animal Care and Use Committee of the University of Western Ontario.
The three cats were trained on two detection and orienting tasks, one that used an acoustic stimulus and one that used a visual stimulus. After training, each cat had a single cooling loop chronically implanted over the dorsal surface of the right SC. The animals were then tested to confirm the effectiveness of the SC loop. Then, auditory cortex of the middle and posterior ectosylvian and anterior and posterior sylvian gyri was removed from the left hemisphere (Fig. 1). Finally, performance on the acoustic localization task was then tested with or without the collicular cryoloop being operational.
Apparatus
Training was conducted in an orienting arena that allowed for the presentation of either acoustic or visual stimuli. The apparatus (Fig. 2) was a semicircular arena (diameter 90 cm) that consisted of 13 pairs of miniature speakers and red, 2-V (DC) light-emitting diodes (LEDs). The speakers (part 25RF006, Mouser Electronics, Mansfield, TX) were 2.5 cm in diameter with a frequency response of 800 Hz to 5 kHz. The speaker/LED combinations were placed 15° apart along 180° of the azimuthal plane. The pairs were located 45 cm from the animal's start position and positioned at the cat's eye level. A food reward tray was located beneath each speaker/LED pair. The speakers emitted broadband noise bursts (100 ms in duration) and were calibrated at 78 dB SPL. Stimuli were generated using a Tucker-Davis Technologies (Alachua, FL) stimulus presentation workstation and SigGenRP stimulus design software. The calibration was conducted with a Larson Davis (Pleasant Grove, UT) model 800B sound level meter (SLM) with a 0.5-in. microphone placed equidistant between the L90 and R90 speakers. An A-weighting was used to determine the background noise level. For the experimental stimulus, we used broadband, white noise bursts rather than pure tones because orienting responses to short broadband noise bursts were previously identified to be much more accurate than responses to tones (Populin and Yin 1998). Testing was conducted in a sound-attenuated room lined with Sonex foam (Illbruck, Minneapolis, MN). Therefore the normal background noise of room ventilation was present, 58 dB(A), and the broadband, white noise burst stimulus was presented 20 dB above background (78 dB). Training was conducted in a dimly lit room and ambient light levels (23 cd/m2) were monitored using an Extech (Tampa, FL) data-logging light meter (model #401036).
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Tasks and training
Each cat was pretrained to stand in the center of the arena and approach the illumination of the red LED at the 0° position. A piece of low-incentive, dry cat chow was then presented from the reward tray below the stimulus. During training, the animal's attention was first attracted to the central LED. Then, the LED was extinguished and the sound was presented at one of the 12 peripheral speakers or the central speaker. After the animal approached the stimulus it received the moist food reward from the food tray below the speakers. Any response other than a prompt direct approach to the appropriate stimulus was scored as incorrect. The cat was conditioned to approach the 0° position when an acoustic stimulus could not be localized and receive the low-incentive food. Premature responses were not scored and went unrewarded. Twenty-eight trials formed a block, with each of the 12 peripheral positions tested twice and the central position tested four times. Ten blocks of trials were collected in each session for a total of 280 trials. Catch trials, where no target stimulus was presented, were randomly conducted. As a control, the animals were also trained to orient to a visual stimulus. For the visual task, testing procedures were identical with the only difference being that the target stimulus consisted of a flashed (100-ms) red 2-V (DC) LED. During the final stages of training and during testing, behavioral procedures remained the same, although the cats wore a loose-fitting harness and a lightweight tether that supported the cooling tubes and microthermocouple wires. The tether, tubes, and wires were connected to a loop directly above the animal. Training was complete when a criterion performance level of 80% correct across the entire field was reached on two consecutive days.
Cryoloop implantation
On the day of surgery, all animals received an antiinflammatory medication [dexamethasone, 1.0 mg/kg, administered intramuscularly (im)] and atropine [0.03 mg/kg, administered subcutaneously (sc)] to reduce respiratory and alimentary secretions. The cannulated cephalic vein permitted administration of anesthetic and the infusion of fluids (2.5% dextrose and 1/2 strength lactated Ringer solution). Sodium pentobarbital (about 25 mg/kg to effect) was infused [intravenously (iv)] to induce general anesthesia. The cat was then installed in a stereotaxic apparatus and prepared for surgery using procedures described elsewhere (Lomber et al. 1999).
Cooling loops fashioned from 23-gauge stainless steel hypodermic tubing (Lomber et al. 1999) were shaped to conform to the dorsal surface of the superior colliculus. The collicular cryoloops were circular with an inside loop diameter of 2.5 mm. Attached to the union of each loop was a microthermocouple. Collicular cryoloops were implanted using standard procedures (Keating and Gooley 1988; Lomber and Payne 1996; Lomber et al. 1999, 2001). During the implantation it was necessary to sever the splenium of the corpus callosum to permit retraction of the cerebral hemispheres and visualization of the collicular surface lying anterior to the tentorium. This procedure disrupted transmission of some acoustic or visual transcallosal fibers (Lomber et al. 1994). Intracranially, the insulated shafts of the cryoloops were in contact with the bony tentorium and exited the cranial vault posteriorly. The cryoloops were fixed to the skull with bone screws and dental acrylic.
After cryoloop implantation, the dura mater was replaced and bone defects around the implanted cooling loops were repaired with bone and Gelfoam. Dermal incisions were repaired with silk sutures that were removed about 10 days later. During the initial period after awaking, the cats were also given buprenorphine analgesic (0.01 mg/kg, sc). Ambi-pen (G.C. Hanford Manufacturing, Syracuse, NY) systemic antibiotic (300,000 units, im) was administered every 2 or 3 days for 1 wk to guard against possible infection. In all cases, postsurgical recovery was uneventful.
Behavioral testing of the effects of SC deactivation
Baseline performance levels were reestablished after cooling loop implantation and before any deactivations, to verify that neither the surgical procedures nor the presence of the cryoloops interfered with performance and to ensure stationarity of motivational and performance states. During testing, the cats wore a harness and a tether that supported the cooling tubes and thermocouple wire. The cat enjoyed full freedom of movement in the arena. Cooling deactivation of the superior colliculus was effected by pumping cold methanol through the lumen of the cryoloop tubing. Cryoloop temperature was monitored continuously by a microthermocouple attached to the union of the loop. Cooling of collicular cryoloops to 2°C was sufficient to deactivate the superficial and intermediate layers of the superior colliculus (Lomber et al. 2001). Orienting data were also collected at higher cryoloop temperatures to assess the effects of partial SC deactivation.
Testing sessions were typically carried out once a day with 10 testing blocks collected in each session. Performance was tested in the presence and absence of cooling the superior colliculus cryoloop and a three-step testing paradigm was used. 1) Baseline data were collected before any cooling. 2) Testing began with cooling deactivation of the collicular cryoloop. 3) Baseline levels were reestablished after cessation of cooling and reactivation of the superior colliculus. Each of the testing steps consisted of at least two blocks of trials. Performance on blocks of trials, or groups of blocks, was compared both within and between testing sessions.
Auditory cortex ablation
Three months after implantation of the SC cooling loops and subsequent testing, auditory cortex of the left hemisphere was ablated. Each cat was prepared for surgery as described for the SC cryoloop implants. A midline incision was made in the scalp and the left temporalis muscle was detached and reflected laterally. A craniotomy was made over auditory cortex and the bone piece was stored in sterile saline. The dura mater was then incised and reflected to expose the cerebrum. The ablations of auditory cortex were made by subpial aspiration and encompassed all of the contiguous regions of acoustically responsive cortex with the intention to remove the anterior ectosylvian gyrus, the middle ectosylvian gyrus, the anterior half of the posterior ectosylvian gyrus, and the dorsal halves of the anterior and posterior sylvian gyri (Fig. 1). The following landmarks were used as borders for the ablations: the middle suprasylvian sulcus, the crown of the posterior ectosylvian gyrus, the middle of the ectosylvian sulcus, and the ventral end of the posterior ectosylvian sulcus (Fig. 1). Saline-soaked sterile gelatin sponges were placed in the cortical defect and, when hemostasis was achieved, the dura and stored bone piece were restored to their normal position. The temporalis muscles were sutured together and the skin incision was repaired. The cats were then recovered using procedures described for the SC cryoloop implantations.
Behavioral testing of the effects of auditory cortex ablation and in combination with SC deactivation
After the ablation of auditory cortex in the left hemisphere, the cats were tested daily for 3 mo. After 3 mo of postablation testing, daily cooling deactivation of the right SC resumed. Cooling deactivation of the right SC was conducted using the three-step testing paradigm described earlier. Most orienting data were collected during cooling of the SC cryoloops to 2°C (to deactivate the superficial and intermediate layers of the superior colliculus; Lomber et al. 2001), although orienting data were also collected at higher cryoloop temperatures to assess the effects of partial SC deactivation.
Terminal procedures
At completion of testing, two cats (SEA1 and SEA2) were anesthetized (sodium pentobarbital, 25–30 mg/kg, iv) and temperatures in the superior colliculus were measured with microthermocouples during cooling of the cryoloops to 10 and 2°C. From these measurements it was possible to map the depth from the collicular surface that contained deactivated neurons. The purpose was to identify the position of the 20°C thermocline [20°C is the critical temperature below which synaptic activity is silenced (Bénita and Condé 1972; Jasper et al. 1970; Lomber et al. 1999)]. Positions between the 20°C thermocline and the cooling loop were at temperatures <20°C and were silenced, whereas positions distal to the 20°C thermocline, relative to the cooling loop, were warmer than 20°C and partially or fully active.
Collicular temperatures during cooling were measured using microthermocouples (150 microns in diameter) manufactured for us by Omega Engineering (Stamford, CT). The microthermocouples were first positioned and then the loop was cooled to several temperatures. This procedure ensured that temperature measurements for a given cryoloop temperature setting were taken at exactly the same sites in the colliculus. For each measurement, the SC was cooled for about 5 min before a recording was made, as occurred in the behavioral component of the study. This protocol was then repeated at multiple, sequentially sampled sets of sites.
After completion of both mappings, the cats were then anesthetized with an overdose of sodium pentobarbital (50 mg/kg, iv) and perfused with fixatives in accordance with the recommendations of the American Veterinary Medical Association Panel on Euthanasia (Beaver et al. 2001). The brains were fixed with 10% formalin, blocked, removed from the cranium, and cryoprotected with 30% sucrose, after which 50-æm-thick coronal sections were cut and stained for Nissl substance, myelin, and cytochrome oxidase.
The third cat (SEA3) received a systemic injection of 14C-2 deoxyglucose (2DG; 100 µCi/kg, iv), as described previously (Payne and Lomber 1999). One day before 2DG administration a venous catheter was inserted into a cephalic vein. During 2DG administration, the cat was fully conscious to maximize uptake. The cat was comfortably restrained in a veterinary cat sack and the inlet and outlet tubes of the SC cryoloop were connected to the cooling circuit. After temperature stabilization at 2°C (about 5 min), the first of four boluses of 25 µCi kg–1 of 2-deoxy-D-[U-14C] glucose was administered. The remaining boluses were injected at 5-min intervals. Ten minutes after the final injection, heparin (2,000 units/kg, iv) and sodium nitrite (1 ml of 0.1% solution, iv) were administered and the cat was deeply anesthetized with sodium pentobarbital (45 mg/kg, iv) and perfused with fixatives in accordance with the recommendations of the American Veterinary Medical Association Panel on Euthanasia (Beaver et al. 2001). The brain was quickly exposed (about 4 min), removed from the skull, blocked, and photographed. The brain was coated with egg albumin and placed in methylbutane (–35°C). After 30 min, the brain was transferred to a –80°C freezer for subsequent tissue processing.
The brain was sectioned in the coronal plane on a cryostat (–20°C) at 35 µm and every fifth section was collected on coverslips. Dried sections were applied to X-ray film and processed using routine procedures (Payne and Lomber 1999). The extent of the deactivated area was then determined by delineating the region of decreased 2DG uptake. Cooling-induced decreases in 2DG uptake are obvious (Payne and Lomber 1999) and require only imaging equipment to assay the gradients on the fringes of the deactivation. For these purposes we used an MCID Elite imaging analysis system (Imaging Research, St. Catherines, Ontario, Canada). The borders of the region of decreased 2DG uptake (>25% reduction) were determined by standardizing the brains with 14C standards (Amersham, Arlington Heights, IL) and calibration curves (Gonzalez-Lima 1992) and by comparing the region with the similar site from a population of normal, nondeactivated brains that were not part of this study. Every fifth section was processed histochemically for the presence of cytochrome as we have done in the past (Payne and Lomber 1996) and adjacent sections were stained using conventional methods for the presence of Nissl bodies or myelin.
Lesion assessment
The location and size of the auditory cortex ablations were assessed directly by examining the defect in the gross brain both immediately after the perfusion and in photographs. In addition, microscopic assessments were made after histological processing and staining for Nissl substance or cytochrome oxidase. The auditory cortex was examined and the remaining regions of cortex were identified using architectonic criteria (Clascá et al. 1997; Kelly and Wong 1981; Rose 1949; Sanides and Hoffman 1969; Sousa-Pinto 1973; Winer 1992) and plotted onto standardized sections illustrated by Reinoso-Suárez (1961). Examples of the cortical lesions reconstructions for the three cats examined in this study are given in Fig. 3. Retrograde degeneration in the thalamus was assessed microscopically and mapped using the designations of Jasper and Ajmone-Marsan (1954) and Berman and Jones (1982).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Ablation reconstruction
In all three cats, the auditory cortex ablations (Fig. 3) removed virtually all the cortex that is generally recognized to be acoustically responsive (Fig. 1). Reconstructions of the auditory cortex ablation show that the cortical tissue removed included all of the anterior ectosylvian gyrus as far rostral as the coronal level A15–16, the full extent of the middle ectosylvian gyrus, the anterior half of the posterior ectosylvian gyrus, and the dorsal halves of the anterior and posterior sylvian gyri (Fig. 3, A–C, gray). The dorsal margin of the ablation was the middle suprasylvian sulcus, the posterior border was the crown of the posterior ectosylvian gyrus, the anterior end of the ablation was anterior to the posterior half of the anterior ectosylvian sulcus, and the ventral border of the ablation tended to be the ventral end of the posterior ectosylvian sulcus. Therefore the ablated region included the classically defined area AI (Reale and Imig 1980), the dorsal zone (Middlebrooks and Zook 1983), the region previously described as the suprasylvian fringe (Beneyto et al. 1998; Niimi and Matsuoka 1979; Paula-Barbosa et al. 1975; Woolsey 1960), the posterior auditory field or area P (Imig et al. 1982; Phillips and Orman 1984), the anterior auditory field or area A (Knight 1977; Reale and Imig 1980), the ventral posterior auditory field or area VP (Imig et al. 1982), the acoustically responsive field of the anterior ectosylvian sulcus (Clarey and Irvine 1986; Meredith and Clemo 1989; Mucke et al. 1982), area AII (Woolsey 1960), the insular area, the majority of the anterior sylvian area as defined by Clascá et al. (1997, 2000), the temporal area (area Te of Clascá et al. 2000), the ventral auditory field (VAF or V; Reale and Imig 1980), the dorsal (dPE), intermediate (iPE), and ventral (vPE) divisions of the posterior ectosylvian gyrus (EPD, EPI, and EPV of Winer 1992), and portions of area PS of Updyke (1986). With the exception of the visual field of the anterior ectosylvian sulcus (AEV), there was little or no involvement of visual or sensorimotor cortices. However, the involvement of this field in the lesion was unlikely to have any bearing on this study because deactivation of AEV does not interfere with orienting to either visual or acoustic targets (Lomber and Payne 2004).
In the thalamus, the ablations resulted in extensive degeneration in both the ventral and dorsal divisions of the medial geniculate nucleus ipsilateral to the cortical ablation. Some degeneration was also evident in all subdivisions of the lateral posterior–pulvinar (LP-Pul) complex as defined by Raczkowski and Rosenquist (1983). These observations are consistent with similar qualitative observations made in earlier studies that performed equivalent ablations of auditory cortex (Casseday and Diamond 1977; Strominger 1969; Whitfield et al. 1972). There was little evidence of any degeneration in the A-laminae, C-complex, medial interlaminar nucleus (MIN), or geniculate wing divisions of the dLGN. Therefore there appeared to be little or no undercutting of visual fibers passing from the dLGN to visual cortex beneath auditory cortex. This observation was behaviorally confirmed by the lack of any deficits in visual orienting behavior after the auditory cortex ablations.
Cortical structure beneath the cooling loops
Dissection and exposure of the brain revealed that the cryoloops were in contact with the dorsal surface of the right superior colliculus. We verified that neither the surgical procedures nor the presence and repeated cooling of the cryoloops disturbed the superior colliculus. In all instances, cytoarchitecture appeared normal (Kanaseki and Sprague 1974) with no signs of damage, necrosis, or gliosis. The only evidence of the presence of cooling loops was small cryoloop contact impressions on the collicular surfaces.
Locus and extent of cooling deactivation
Thermal readings taken from two cats (SEA1 and SEA2) revealed that cooling of the superior colliculus cryoloops to 10°C created a 20°C thermocline at a depth of about 1.2 mm (Fig. 4A), which marks the boundary between the fully inactive and active zones (Lomber et al. 1999). Both the stratum griseum superficiale (SGS) and a major portion of the stratum opticum (SO) are contained between this boundary and the surface and we infer that neurons in this region were deactivated (gray region in Fig. 4A). This inference was substantiated in the third cat (SEA3) because cooling of the SC cryoloop to 10°C reduced 2DG uptake throughout SGS with little impact on SGI (compare Fig. 5A to Fig. 5B). Reduction of the cryoloop temperature to 2°C "pushed" the 20°C thermocline to a depth of 2.2 mm and toward the lower border of stratum griseum intermediale (SGI; Fig. 4B). Accordingly, we infer that most of the neurons in SGS, SO, and SGI were silenced when the loop temperature was reduced to 2°C (gray region in Fig. 4B).
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Acoustic orienting behavior
SUPERIOR COLLICULUS COOLING DEACTIVATION. Both before (Fig. 6A) and after (Fig. 6B) implantation of the superior colliculus cryoloop over the dorsal surface of the right SC, all three cats (Fig. 6, i–iii) were highly proficient at detecting and orienting toward the broadband, white noise burst emitted from any of the 13 speakers positioned throughout the 180° field. The only positions showing any weakness in orienting were the left and right 90° stimulus locations, where performance was slightly imperfect (Fig. 6, A and B). The similarities between the pre- and postimplant performance indicate that neither the surgical implantation of the cooling loops nor the continual presence of the loops interfered with accurate sound localization.
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, 2002) and confirmed the effectiveness of the SC cryoloop in each cat.
We cooled the right SC to 2 ± 1°C because earlier studies had determined that cooling an SC loop to 2 ± 1°C would fully deactivate both the superficial and intermediate layers of the SC (Lomber et al. 2001). In the present study, we sought to determine the minimum level of cooling necessary to cause a complete impairment of acoustic orienting into the contralateral hemifield. In each animal, we systematically decreased the temperature of the SC cryoloop in 3°C increments. Figure 7 shows the results from this experiment. At SC cryoloop temperatures 
11°C, there was no decrease in accurate acoustic orienting responses to any positions in the contralateral hemifield (Fig. 7, A and B). However, at temperatures <11°C, the size of the acoustic orienting deficit in the contralateral field increased as the temperature of the SC cryoloop decreased (Fig. 7). This contralateral (left) hemifield deficit was temperature-dependently graded from periphery to center (Fig. 7, C and D). Decreasing loop temperatures never affected accurate acoustic orienting into the ipsilateral (right) hemifield (Fig. 7). The deficit was complete when the loop temperature reached 2°C (Fig. 7E). This result was consistent for all three cats.
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Deactivation of the right superior colliculus after the ablation of the left auditory cortex (Fig. 8C) yielded a fundamentally different result from that identified during deactivation of the right SC before the removal of left auditory cortex (Fig. 6C) in the same animal. Before removal of the auditory cortex, deactivation of the right SC resulted in a profound orienting deficit specific to the contralateral (left) field (Fig. 6C). After the removal of left auditory cortex, deactivation of the right SC did not cause an orienting deficit in the contralateral field (Fig. 8C). Instead, this deactivation nullified the deficit caused by the left auditory cortex ablation and acoustic orienting responses were restored into the right hemifield. These findings are similar to the original results described by Sprague (1966) in the visual system where it was described how deactivation of the contralesional SC nullifies the effects of the visual cortex ablation and restores visual orienting responses into the cortically blind hemifield. Possible mechanisms mediating this acoustical version of the "Sprague Effect" are considered in the DISCUSSION.
Restoration of the acoustic orienting responses during cooling of the SC was temperature-dependently graded from center to periphery (Fig. 9). At higher cryoloop temperatures the restoration in orienting was only partial (Fig. 9, C–E). At the lowest temperatures, when restoration was complete, a minor deficit in the far periphery of the left hemifield could be identified (Fig. 9F). Figure 10 graphically shows the gradual restitution of acoustic orienting over a 12°C range of increased cooling deactivation of the superior colliculus. Therefore because an SC cryoloop temperature of 2°C is required for a complete restoration of acoustic orienting responses (Fig. 9), and cooling an SC cryoloop deactivates SGS, SO, and SGI, we can now deduce that restoration of acoustic orienting responses requires the deactivation of SGS, SO, and SGI. Merely cooling an SC loop to 10°C, which deactivates only SGS and SO, is not sufficient to fully restore acoustic orienting responses.
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Although the ablations of auditory cortex had a profound effect on acoustic orienting into the contralateral hemifield (Fig. 6B), the ablation did not have any impact on visual orienting into the same hemifield (Fig. 11) and all responses were robust. These results confirm the specificity of the ablation on acoustic processing. These results also confirm that the motor reporting system was operational after the ablation of auditory cortical areas.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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We obtained four major results from our examination of acoustic and visual orienting responses after removal of auditory cortex during cooling deactivation of the contralesional superior colliculus.
In conclusion, similar to the visual system, after auditory cortex ablation, deactivation of the contralesional superior colliculus results in a restoration of acoustic orienting responses. Therefore the "Sprague Effect" can be identified in both visual and acoustic modalities.
Experimental considerations
In this study we positioned the SC cooling loops and tested their function before performing the ablations of auditory cortex. This procedural order consideration was critical for an accurate interpretation of the results. Although we hypothesized that deactivation of the contralesional superior colliculus would reverse the orienting deficits caused by unilateral destruction of auditory cortex, we expected that three results were possible: 1) that we would confirm the hypothesis; 2) that cooling of the SC would have no impact on behavior after the auditory cortex lesions (the "null" hypothesis); or 3) that cooling the SC would have an additive effect and there would be an orienting deficit in both hemifields. Regardless of the procedural order, in both the first and third possibilities, we would know that the SC cooling loops were functioning because a discernable change in behavior would be observed. For the first possibility, the deficit would be reversed and for the third possibility the deficit would become greater, including both hemifields. However, if the auditory cortex had been ablated before the SC loop implantation and if the second possible result (the "null" hypothesis) was identified, it would be impossible to determine whether the result was legitimate or whether the cooling loop was not adequately deactivating the SC. Therefore in this experiment it was critical for the SC loop to be implanted first and tested to verify that it was fully functional, before the ablation of auditory cortex.
Contributions of the superior colliculus to orienting behaviors
The superior colliculus (SC) plays an important role in orienting of the head and eyes to visual or acoustic stimuli (Apter 1946; Hess et al. 1946; Lomber et al. 2001; Sprague and Meikle 1965). Internally, the SC can be divided into superficial, intermediate, and deeper layers (Kanaseki and Sprague 1974), with the superficial layers connected almost exclusively to visual structures (Graybiel 1975; Harting and Guillery 1976; Harting et al. 1992), whereas intermediate and deeper layers receive afferents from multiple sensory cortices (visual, auditory, and somatosensory; Clemo and Stein 1984; Harting et al. 1992; Meredith and Clemo 1989; Tortelly et al. 1980) as well as brain stem sources (King et al. 1998). Accordingly, superficial layer neurons are exclusively visual, whereas intermediate and deep neurons respond to visual, acoustic, and somatosensory stimuli and many respond to more than one modality (Meredith and Stein 1986; Peck 1990; Stein et al. 1976; Wallace et al. 1993). Furthermore, visual space was previously identified to be mapped in both the superficial (Feldon et al. 1970) and intermediate and deep (Meredith and Stein 1990) layers of the SC, whereas auditory space is mapped in only the intermediate and deep layers (Middlebrooks and Knudsen 1984; Palmer and King 1982). Therefore it was not surprising when we identified that cooling deactivation of the SC had to extend into the intermediate layers (SGI; Fig. 4B) to produce a deficit in orienting to targets presented in the contracooled field. In contrast, earlier studies reported that deactivation of only the superficial layers (SGS) is required to produce a deficit in orienting to visual targets presented in the contracooled field (Lomber et al. 2001). Therefore results of the present behavioral study agree with the earlier behavioral and electrophysiological reports that showed that normal functioning of the superficial layers (SGS and SO) is necessary for proficient visual orienting and that normal functioning in the intermediate and deep layers (SGI) is necessary for accurate acoustic orienting.
Previous studies using physical ablations of the superior colliculus described ipsiversive turning of the cats after unilateral lesions (Sprague and Meikle 1965). However, this condition was generally reported to be short-lived. The animals quickly recover from the surgery and the ipsiversive turning is greatly reduced after 1 wk postop and generally absent after 1 mo (Sprague 1996; Sprague and Meikle 1965). Using unilateral reversible deactivation of the superior colliculus we did not observe any profound ipsiversive turning of the animals during repeated daily cooling deactivation (Lomber et al. 2001; present study). In agreement with these earlier studies (Sprague 1996; Sprague and Meikle 1965) we qualitatively observed shorter orienting latencies to the ipsicooled side and an absence of orienting contralaterally.
Although the consequences of unilateral SC ablations on acoustic orienting have been well documented, only two studies examined the consequences of bilateral SC deactivations on acoustic localization (Lomber et al. 2001; Tunkl 1980). In agreement with the present investigation, both of these studies show that unilateral collicular deactivations result in acoustic orienting deficits confined to the contralesional field (Lomber et al. 2001; Tunkl 1980). However, a bilateral ablation (Tunkl 1980) or cooling (Lomber et al. 2001) of the SC both show that these deactivations do not result in bilateral deficits. In fact, after deactivation of one SC, the additional deactivation of the contralateral SC restores acoustic orienting to the previously impaired hemifield. Overall, the only impairments are in the peripheral-most positions (left and right fields beyond 60°; Lomber et al. 2001). This restoration occurs only when both the superficial and intermediate layers of the SC are deactivated on both sides (Lomber et al. 2001). Therefore deactivation of the contralateral superior colliculus not only can restore acoustic orienting after a cortical ablation, but it can also restore acoustic orienting after an SC deactivation. This restoration does not occur at the cortical level because large bilateral lesions of all acoustically responsive cortices produce bilateral deficits in carnivores and primates (Girden 1939; Heffner 1978, 1997; Heffner and Heffner 1990; Kavanagh and Kelly 1987; Neff 1968; Neff et al. 1956; Ravizza and Diamond 1974; Strominger 1969; Thompson and Welker 1963).
Contributions of auditory cortex to acoustic orienting
For behavioral tasks involving sound localization and accurate orienting to an acoustic stimulus, the effects of cortical lesions are fairly well documented. Large unilateral lesions involving primary auditory and much of the remaining acoustically responsive cortex result in sound localization deficits confined to the contralateral hemifield. This result was previously documented in cats (Casseday and Diamond 1977; Cranford et al. 1971; Jenkins and Masterton 1982; Neff 1968; Neff et al. 1956; Strominger 1969; Thompson and Welker 1963; Whitfield et al. 1972; present study), ferrets (Kavanagh and Kelly 1987), dogs (Girden 1939), and old-world monkeys (Heffner 1997). These ablations result in a large area of acoustical space in which the subject is unable to localize sounds (Jenkins and Masterton 1982), encompassing nearly all the contralateral hemifield. From our observations, it appears that the border between the impaired and unimpaired hemifields is relatively sharp. Heffner (1997) suggested that a small region, not exceeding 18°, along the medial aspect of the impaired hemifield was a region of reduced localization ability that was not impaired to the same degree as the more lateral aspects of the impaired hemifield. If this "transitional" region between the unimpaired and impaired hemifields exists, then, as a result of the resolution of our testing paradigm, we suggest that it must be <15°.
Although the forebrain plays a significant role in orienting to an acoustic stimulus in primates and carnivores, the forebrain does not seem to play such a significant role in lower species such as rats or barn owls, two species in which sound localization has been extensively studied. Bilateral destruction of primary auditory cortex in the rat does not result in orienting errors to acoustic stimuli (Kelly 1980; Kelly and Glazier 1978; Kelly and Kavanagh 1986). Furthermore, when these ablations are expanded to include all regions of acoustically responsive cortex, no significant sound localization deficits can be identified (Kelly 1980; Kelly and Glazier 1978; Kelly and Kavanagh 1986). In the barn owl, lesions of the forebrain do not significantly impair accurate orienting and approach to an acoustic stimulus as long as the midbrain (optic tectum) is intact (Knudsen et al. 1993). Subsequent studies identified that the forebrain of the barn owl is critical for accurate orienting to the remembered location of a sound source (Knudsen and Knudsen 1996), whereas the optic tectum appears to be critical for stimulus-guided responses to a sound source (Knudsen and Knudsen 1996).
In the cat, whereas large ablations of acoustically responsive cortex produce a deficit in the contralesional hemifield, much smaller deactivations also produce contralateral impairments. Removal or deactivation of primary auditory cortex (AI), the posterior auditory field (PAF), or the auditory field of the anterior ectosylvian sulcus (AES) produces sound localization deficits in the contralateral hemifield (Casseday and Diamond 1977; Jenkins and Masterton 1982; Jenkins and Merzenich 1984; Malhotra et al. 2004; Strominger 1969; Whitfield et al. 1972). However, the effects of the large lesions appear to be more profound than the smaller individual deactivations. For example, as noted in Malhotra et al. (2004), during unilateral deactivation of AI, PAF, or AES, the animals would continue to orient into the impaired hemifield and make an incorrect choice. This contrasts with the results of the present study in which the cats failed to orient into the impaired hemifield. The animals would choose the default (0°) position when the stimulus was presented in the impaired field. The larger lesions seemed to produce a form of acoustic neglect (Clarke and Thiran 2004). Therefore reversal of the acoustic orienting deficits by deactivating the contralesional superior colliculus is even more striking.
Task-specific deficits
SUPERIOR COLLICULUS.
In the present study we examined the conditioned ability of cats to orient and approach an acoustic target. However, it is also possible to study unconditioned responses to a sound source because cats will reflexively orient their heads to a white-noise sound burst. Unfortunately, we were unable to identify any studies that directly compared sound localization using head orienting versus whole body orienting during deactivations of the superior colliculus. The only information available on reflexive head orienting was from the study of Thompson and Masterton (1978) that examined unconditioned reflexive head orienting to a white-noise burst, in one cat, after unilateral damage of the superior colliculus. Thompson and Masterton (1978) reported that a unilateral lesion of the SC did effect head orienting to visual stimuli, but did not effect head orientation to sound, except for lengthening the latency of the response to the contralesional side. The results from this study are difficult to interpret because the lesion of the SC was not complete. We previously described that deactivation of only the superficial layers of the SC will impair orienting to visual stimuli, whereas deactivation of the entire SC, including the intermediate and deeper layers, is required to impair orienting to acoustic targets (Lomber et al. 2001). Thompson and Masterton (1978) reported that "a lesion of the superior colliculus that results in all the signs of dysfunction for visual orientation need not interfere with the essential elements of head orientation to sound." Although the results of Lomber et al. (2001) agree with this statement, it also establishes the likelihood that although the SC lesions of Thompson and Masterton (1978) were sufficient to reveal visual deficits, they were likely incomplete and may have been insufficient to produce acoustic deficits.
AUDITORY CORTEX.
In sound localization tasks, the most common reporting mechanism has been to use orienting of the head or whole body toward the stimulus, which is often accompanied with an approach to the sound source. Consistent in these studies are the findings that unilateral deactivations of all acoustically responsive cortex impair sound localization within the hemifield contralateral to the deactivated cortex and that bilateral ablation of auditory cortex impairs sound localization throughout the entire field (Heffner and Heffner 1990; Jenkins and Masterton 1982; Kavanagh and Kelly 1987; Neff et al. 1956; present study). Unfortunately, we were unable to identify any studies that compared sound localization using head orienting versus whole body orienting during deactivations of auditory cortex. Beitel and Kaas (1993), who examined unconditioned head orienting responses to white-noise bursts after both unilateral and bilateral ablations of auditory cortex in its entirety, found that bilateral removal of auditory cortex severely impaired the ability of cats to accurately orient to a sound source. However, in cats with unilateral ablations of auditory cortex, there were no deficits in orienting to sounds presented in either hemifield (Beitel and Kaas 1993). This result is contrary to the results using conditioned orienting tasks that found that unilateral destruction of all acoustically responsive cortex resulted in sound localization impairments in the contralateral, but not ipsilateral, hemifield. Therefore although the conditioned and unconditioned orienting deficits are consistent for bilateral ablations of auditory cortex, profound conditioned orienting deficits follow unilateral ablations of auditory cortex, whereas no unconditioned orienting deficits follow similar unilateral ablations.
Possible mechanisms mediating the acoustic Sprague Effect
Within the visual system, studies have sought to determine whether the restoration of visual orienting responses is triggered by ablation of collicular neurons that project axons through the intercollicular commissure or whether the lesion of the intercollicular commissure disrupts projections from noncollicular sources that also course through the same commissure. Wallace et al. (1989) concluded that the restoration in visual orienting was mediated by the severance of axons from noncollicular sources that course through the posterior intercollicular commissure. Subsequent experiments (Wallace et al. 1990) showed that small ibotenic acid ablations of the rostrolateral substantia nigra pars reticulata, and possibly the overlying ventral zona incerta, consistently produced a visual recovery, whereas lesions of the other collicular afferents from mesencephalic sources did not. Wallace et al. (1990) postulated that damage to the crossed nigrocollicular projection disinhibits the superior colliculus ipsilateral to the cortical lesion and the resultant excitation leads to recovery. Overall, these results show the significance of contralateral mesencephlic structures in maintaining a deficit in orienting into a visual hemifield contralateral to a large visual cortical lesion. More recent studies showed that the substantia nigra inputs to the SC involved in striatal–nigral–collicular circuits project to the contralateral colliculus through the collicular commissure and spread through the SO before descending into the intermediate layers (McHaffie et al. 2005, 2006). Therefore it would seem possible that cooling the superficial layers (SGS and SO) could inactivate these nigrotectal fibers while disrupting visual but not auditory orienting functions. It would thus seem likely that the mechanisms underlying the visual and acoustic versions of the Sprague Effect may be different.
Much of the anatomical information available to assist in deciphering of the circuitry underlying the Sprague Effect in the visual system does not yet exist in the auditory system. Although some information on auditory cortical projections to the SC is available (Meredith and Clemo 1989; Tortelly et al. 1980), we were unable to locate information on auditory cortical projections to the substantia nigra, striatum, or basal ganglia. Presumably, projections from these structures to the tectum are involved in mediating the recovery of acoustic orienting responses.
Past studies concerning the causes of the "Sprague Effect" concentrated on disinhibition as the prime mechanism mediating the restoration in orienting performance. Such a view is supported by experiments that show that lesion of one superior colliculus reduces the impact of suppressive surrounds of neurons in the contralateral superior colliculus (Waleszczyk et al. 1993)—it is tempting to invoke a similar rationale to explain the results of the present study. For example, from our deactivations we could speculate that neurons deeper in the superior colliculus that receive signals from the superficial layers (Behan and Appell 1992), including those that project to the opposite side (Behan and Kime 1996a), are less active than normal. Based on electron microscopic characterization of intercollicular axon terminals as being of both the excitatory asymmetric and inhibitory symmetric types (Behan 1985), the net effect of cooling is both to depress excitation and to disinhibit target neurons in the deep layers of the contralesional superior colliculus (Behan and Kime 1996a,b) and to effect a restoration in orienting.
Overall, these observations point to the complexity of interactions between brain structures and pathways and suggest that the acoustic orienting deficits may not arise simply by the interference with circuitry on one side of the brain. Important data suggest that imbalances in the levels of activities of structures on the two sides of the brain may also be an important factor because structures in the normally functioning side may gain preferential control over behaviors arising from diminished competition from the opposite side (Kinsbourne 1987; Mesulam 1981; Rizzolatti and Berti 1990; Sprague 1966; Vallar 1993). In addition, an important aspect of SC interactions that may additionally contribute to the imbalanced levels of activity and to deficits in orienting is the prominent and reciprocal inhibitory pathways between the two superior colliculi (Behan 1985). Analyses of circuits and modeling of reciprocal influences suggest that as activity is depressed in one SC, activity increases on the uncooled side because of its release from contralateral inhibition (Hilgetag et al. 2001; Lomber and Payne 1996).
Conclusions and future directions
In the present study, we concluded that the "Sprague Effect" is not unique to a particular sensory system and deactivation of the contralesional SC can restore either visual or acoustic orienting responses into an impaired hemifield after cortical damage. The next step in these investigations will be to examine whether the deficits found after individual deactivations of specific cortical regions (such as AI, PAF, or AES) that cause inaccurate orienting to acoustic targets can be reversed after deactivations of the contralesional superior colliculus. If these deficits can also be reversed then it would be possible to devise experiments involving chronic recording from the superior colliculus during both individual and combined deactivations of ipsilateral cortical and contralateral collicular sites. These examinations would provide information on changes in neural activity in different layers of the superior colliculus after these deactivations and help in the dissection of the mechanisms and microcircuits underlying the acoustic "Sprague Effect."
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. G. Lomber, Centre for Brain and Mind, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada (E-mail: steve.lomber{at}uwo.ca)
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