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1Department of Anatomy and 2Neuroscience Training Program, University of Wisconsin-Madison Medical School, Madison, Wisconsin; and 3Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York
Submitted 8 July 2005; accepted in final form 14 August 2005
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ABSTRACT |
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INTRODUCTION |
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; Destexhe and Marder 2004; Poncer 2003; Tsodyks and Gilbert 2004), but can also have mixed (Hodzic et al. 2004) or detrimental effects (Romanelli and Esposito 2004; Sah et al. 2003). We are only beginning to understand the changes induced by natural sensory stimuli and how the functions of whole circuits in active vertebrate brains may be altered by neuroplastic change.
Plasticity is present in the visual system, and long-term neuroplastic changes have been shown in the adult visual pathways (Castro-Alamancos and Calcagnotto 1999; Heynen and Bear 2001; Otsu et al. 1995; Salami et al. 1999). Plasticity is often associated with perceptual learning tasks (Tsodyks and Gilbert 2004), but sensory stimulation, itself, appears to alter visual responses outside of learning paradigms. A common finding is long-term response sensitization, that is, a persistent increase in responsiveness resulting from repeated visual stimulus presentation. Sensitization has been reported in human psychophysical studies (Seitz and Watanabe 2003; Watanabe et al. 2001) and in late components of the rat occipital–evoked potential (Dyer 1989). Clinical reports (Appleton et al. 2000; Gastaut et al. 1962; Harding and Jeavons 1994; Walter and Walter 1949) have also raised the possibility that repeated exposure to strobe stimuli may sensitize responses. Taken together, these results indicate that individuals may acquire a sensitized response through long-term plastic processes following repeated exposure to photic stimulation.
Stroboscopic stimulation was effective in previous basic science and clinical studies providing evidence of long-term change (e.g., Appleton et al. 2000; Dyer 1989; Gastaut et al. 1962; Harding and Jeavons 1994; Walter and Walter 1949). In addition, trains of electrical shocks to the thalamus or cortex produce a form of short-term neuroplasticity, the thalamocortical augmenting response (Bazhenov et al. 1998a,b; Castro-Alamancos and Connors 1996a–c; Dempsey and Morison 1943; Steriade and Timofeev 1997), which in some cases can lead to self-sustaining paroxysmal activity (Steriade et al. 1993). Thus we theorized that trains of intense photic stimulation might be efficacious in inducing neuroplastic change leading to photoparoxysmal activity.
To test this, we exposed ordinary laboratory rats to strobe trains and evaluated their response by means of electrocorticographic recording. Repeated photic exposure in this intact, mature vertebrate nervous system led to induction of a long-lasting sensitization of visual response that exhibited spike-wave morphology and generalized across the brain. We evaluated the acquisition and expression of this sensitized response.
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METHODS |
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Normal 200- to 500-g young adult commercially obtained (Harlan Sprague-Dawley) outbred rats were used. Experiments were conducted with 30 male Sprague-Dawley rats. Essential findings were confirmed additionally in two female Sprague-Dawley rats, two male Long-Evans rats (Blue Spruce), and two male Wistar Rats. All rats were in good health and exhibited normal behavior before testing with no history of epileptiform activity.
The experimental protocol was approved by the University of Wisconsin Animal Care and Use Committee. Rats were maintained on a 12-h:12-h light/dark cycle in standard laboratory animal housing at the University of Wisconsin, with food and water ad libitum. Animals were tested experimentally in the morning, within 2–6 h after the lights turned on at 0600 hours.
Surgical procedures
Before surgery for implantation of chronic recording electrodes, animals were administered a combination of ketamine (60–90 mg/kg, ip) and xylazine (5–10 mg/kg, ip) to effect. Supplemental doses of 
25–33% of the original dose were readministered as necessary to maintain deep anesthesia throughout the surgical procedure, with xylazine supplements administered one-third as often as ketamine supplements. Rectal temperature was maintained throughout surgery at 37.5–38.0°C using a feedback-controlled heating blanket.
The deeply anesthetized rat was placed in a stereotaxic apparatus and prepared for aseptic surgery. Surgical instruments were wet sterilized. The dorsal surface of the head overlying the brain was shaved and bathed in povidone/iodine solution. The skull was exposed by a midline incision and retraction of overlying tissues. Craniotomies <1 mm diam enabled insertion of electrographic recording electrodes at four predetermined sites, bilaterally from occipital to frontal cortex (occipital 2.0 mm, 5.0 mm, 8.0 mm, frontal 11.0 mm anterior to lambda; ±2.0 mm lateral; Paxinos and Watson 1986). Craniotomies for ground and reference electrodes were placed over the cerebellum. We evaluated the suitability of this commonly used reference location (e.g., Meeren et al. 2002) in preliminary tests by recording from it against reference electrodes in muscle and contralateral cerebellum. There was no evidence of any visually related response from the electrode overlying cerebellum. At each craniotomy site, the uninsulated tip (0.5 mm) of a strand of 30-gauge stainless steel ultraminiature wire (Cooner) was bent at a right angle, placed flat on the dura, and held in place with miniature stainless steel or Teflon screws tapped into the skull through the craniotomy. Wires exiting the craniotomy fed into one end of a miniature connector (Ginder), and the assembly was secured to the skull with additional stainless steel screws and dental acrylic. Wound margins were closed (4-0 nylon) and treated with a broad-spectrum antibiotic ointment and 1% lidocaine. Animals were administered buprenorphine (0.05 mg/kg, sc) postoperatively.
Electrocorticographic recording
Signals arising from the miniature connectors on the rat skull fed into a multi-channel Grass EEG amplifier model 8–16 and band-pass filtered between 1 and 70 Hz. Stimulus presentation and digitized data collection were under computer control (Brainware, TDT). Signals were collected at 25,000 samples/s and computer analyzed typically with 1,000 samples/s (MATLAB and NeuroExplorer).
Experimental design
Experimentally naïve rats were introduced to the experimental environment, minus the strobe light, 1 wk after surgery. Rats were kept in their home cages at all times and preadapted to minimize the incidence of exploratory behavior during recording. Previous studies showed that driven thalamocortical oscillations, paroxysmal responses, and seizures in photosensitive individuals are affected by behavioral state and that exploratory movement or its EEG correlate, theta activity, are related inversely to response amplitude (Bigler 1977; Castro-Alamancos and Connors 1996b; Dyer 1989; Gastaut et al. 1962; Hishikawa et al. 1967). The 3-day adaptation period, with one session daily, allowed rats to become familiar with all aspects of the experiment before the introduction of strobe flashes, provided confirmation that electrodes were working properly, and enabled examination of electrographic recordings before introduction of the strobe stimulus. No rats exhibited spontaneous spike-wave responses or other seizure abnormalities during the adaptation period.
Rats were brought to the quiet recording room in their clear, plastic home cages. Low-level room lighting (<5 cd/m2) was maintained (e.g., Gastaut et al. 1962; Hishikawa et al. 1967; Leroy and Roussel 1961). The home cage (length 0.5 m x height 0.21 m x width 0.27 m) was placed inside the recording chamber (0.55 x 0.4 x 0.4 m), lined on all sides with mirrors to ensure visual stimulation regardless of the position of the rat. Long, lightweight overhead wires connected the recording apparatus to the headmount. Rats were otherwise completely unrestrained.
After adaptation sessions, experimental sessions with strobe lights commenced. Each session began with 1 h of electrocorticographic (ECoG) recording without stroboscopic stimulation during which baseline data were collected. We then initiated trains of stroboscopic stimulation. Data were recorded continuously before, during, and after each train of strobe flashes, which we refer to as a "trial." Intertrial intervals during which no stimulation occurred ranged from 30 s to 1 min. Experimental sessions typically comprised 20–40 strobe trials, but extended 
180 trials for experiments that used pharmacological manipulation or multiple strobe conditions. Experimental parameters were kept constant within experiments. Thus the strobe portion of the experiment ranged from 25 min to 1.5 h, with one session conducted per day.
Activity of the rat was monitored through video surveillance and direct observation. Most data were collected while rats were in a quiet waking state. Data collection was suspended during episodes of protracted, active movement or if rats closed their eyes to sleep.
Visual stimulation
Stroboscopic flash stimuli (10 µs) were generated with a standard Grass photostimulator (Model PS33). The stroboscope was positioned centrally over the recording chamber, with the front diffusing surface of the lamp level with the top of the recording chamber. An integrating photometer was used for luminance calibration; luminance of reflected light from the stroboscope flash within the animal cage measured 5.1 cd·s/m2 (see Fig 12, x-axis). Variations in strobe intensity were accomplished by means of neutral density filters in front of the strobe; this eliminates confounding spectral changes in the strobe flash that occur if intensity is manipulated by varying current to the strobe (cf. Riggs 1965). The strobe light was triggered externally by the computer, enabling precise control of temporal stimulus frequency (1–30 Hz) and stimulus train duration (0.5–6 s). Preliminary results suggested large magnitude responses were elicited with 8-Hz stimulation, and the shortest strobe train at which response incidence and duration appeared maximized was 1–2 s (see Response quantification). Thus 1- to 2-s trains of 8-Hz stroboscopic stimulation were chosen as the standard stimulus in most experiments.
Response quantification
The emergent spike-wave response varied in both amplitude and duration. For quantification, response magnitude was calculated as the rectified and integrated ECoG voltage during the period of strobe stimulation.
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RESULTS |
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Repeated exposure to trains of strobe flashes led to a progressive change in the electrographic responses recorded over rat cortex. Figure 1 shows responses from occipital cortical electrodes in one rat on the first and third days of exposure to the photic stimulus. The rat displayed simple photic responses during initial trials on day 1 (Fig. 1A, day 1, trial 1; Fig. 1B, day 1). These ranged from a weak, irregular periodic response to photic driving, characterized by rhythmic, low-to-moderate amplitude, occipitally recorded sinusoidal-shaped responses at the temporal frequency of the strobe. As strobing trials continued on day 1, however, the strobe-driven electrographic response exhibited cycles of increasingly higher amplitude and transient spikes (<50 ms width; Fig. 1A). By the end of day 1 (20–40 strobe trials) and on subsequent days, the waveform on growing number of trials assumed a spike-wave morphology (e.g., Fig. 1B, day 3). The spike-wave response was observed only in conjunction with strobing and did not occur spontaneously. Additional results showed that implantation of electrodes, by itself, did not produce sensitization. Six rats were implanted surgically, but exposure to the strobe regimen was delayed 3 days to 3.5 wk. Rats underwent the standard adaptation procedure followed by the strobe regimen. No sensitized responses were evident on initial strobe exposure, and all rats followed the standard time-course of sensitization on exposure to the strobe regimen.
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CHARACTERISTICS OF THE SENSITIZED RESPONSE. The spike-wave response differed from the common photically driven response in its distinct spike-and-wave morphology and in amplitude (Figs. 2 and 3). Spike-wave responses were significantly larger in magnitude than the common photic responses observed on adjacent trials in the same sensitized rat (unpaired t-test with Welch correction, P < 0.0001). There was no apparent relation between the magnitude of the eventual spike-wave response and the photic response observed in initial trials of the experiment; rats that initially displayed a weak visual response could nevertheless develop a robust spike-wave response (Fig. 2).
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Termination of a spike-wave episode is characterized by a diminution of spike-wave amplitude of variable time-course that could occur rapidly across a few spike-wave discharges or over a more protracted period.
EPILEPTIFORM NATURE OF THE SENSITIZED RESPONSE. Throughout the course of the sensitization experiments, behavioral alterations were not evident in animals during spike-wave episodes. There was no clear pattern of blinking or synchronized movement. No motor convulsions were observed. Although it seemed at times that there were behavioral pauses during a response, this was not observed consistently and was difficult to evaluate given the brief duration of the episodes and the usually calm state of the animal during recording.
While the sensitized response lacked a behavioral correlate, it displayed a number of electrographic epileptiform characteristics. In addition to the spike-wave morphology, the response generalized across cerebral cortex in every rat. Electrographic electrodes arrayed from occipital to frontal cortex recorded synchronized large amplitude spike-waveforms (Fig. 4). The response tended to be occipitally dominant, with the spike-waveform often appearing first in the occipital leads and secondarily in the other leads, but this varied across rats and across trials within the same rat. In addition to generalization, the response exhibited persistence beyond the end of the strobe period (see below).
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) (Fig. 5). Ethosuximide dosage (100 mg/kg, ip) was the same as that used therapeutically in models of generalized absence seizures in rodents (Snead 1992) and had no gross effect on animal behavior during recording. Strobe-response data were collected before and 30–60 min after administration of ethosuximide in three rats that had fully acquired the sensitized response. The percentage of trials in which spike-wave responses occurred dropped substantially, from 73 to 13%, after ethosuximide treatment. The infrequent spike-wave responses that persisted in the ethosuximide condition (Fig. 5, *) were observed only with longer duration strobe trains (2 s) and were smaller in amplitude than control responses in the same rats. The duration and latency to response were also affected. Average duration of spike-wave response with ethosuximide was significantly shorter than control duration in the same rats (ethosuximide, 6.5 spike-wave discharges per episode vs. control, 10.3 spike-wave discharges; paired t-test, P < 0.004). Average latency to spike-wave response with ethosuximide was significantly longer than control latency (ethosuximide, 9.5 strobe flashes vs. control, 5.0 strobe flashes to 1st spike-wave discharge; paired t-test, P < 0.002). Injections of vehicle solution alone had no effect on spike-wave parameters (paired t-test, all P > 0.05).
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The time-course of acquisition of the sensitized response was similar when the data were quantified alternatively by counting the number of spike-wave discharges or by calculating the spectral power of the response at 8 Hz. Thus rats with 3 or more successive days of strobe regimen exposure were defined as having fully developed spike-wave responses. Further inspection indicated the increase in overall response magnitude during acquisition reflected a change in incidence and number of individual spike-wave discharges in an episode (duration) combined with increased amplitude of spike-wave discharges making up an episode.
Previous study of paroxysmal visual responses or driven oscillations showed suppression of response with exploratory behavior (Bigler 1977; Castro-Alamancos and Connors 1996b,c). Our observations indicated a similar decline in incidence of the sensitized response when animals were exploring actively. The current protocol was designed to minimize and control for such state-dependent factors (cf. Dyer 1989). However, it remained possible that the observed electrocorticographic change corresponded to change in behavioral state. To test for this, we used a theta index measure of activity level in electrical recordings for quantification of the incidence of exploring-type behavior (cf. Bland 1986; O'Keefe and Recce 1993; Skaggs et al. 1996). The theta index was defined as the percentage of power in the 5- to 9-Hz band of the spectral composition of the prestrobe portion of the ECoG on each trial.
Theta band analysis confirmed that variation in active exploring was controlled during acquisition of sensitization (Fig. 6B). Linear regression analysis revealed no relation between theta index and trial number (r = 0.149, P > 0.1). Thus while day 1 yielded significant change in the magnitude of the strobe-driven response (Fig. 6A), the day 1 theta index curve was unchanged across trials (Fig. 6B). Additional regression analyses of prestrobe activity similarly revealed no relation between the changes observed across trials and comparable measure in other ranges of frequencies (1–5, 10–20, 20–100, 40–100, and 40–70 Hz; all P > 0.1)
TIME-COURSE OF RETENTION OF THE SENSITIZED RESPONSE. The sensitized spike-wave response, once acquired, persisted across subsequent test days. To evaluate retention over time, we tested rats after gaps in exposure to the daily strobe regimen. Figure 8 shows average response magnitude as a function of days (note log scale) elapsed since rats with fully acquired spike-wave responses were last exposed to the strobe regimen. We limited quantification to four trials in a rat's daily session, which was sufficient to quantify the ECoG magnitude while minimizing the effects of strobe exposure on reacquisition of sensitization (cf. Fig. 6A). Sensitization, as indicated by response magnitude, remained high in test sessions 0–2 wk after previous testing. However, longer duration periods without strobe exposure resulted in a drop in response magnitude to levels observed in naïve rats on their first day of strobe exposure (Fig. 8, naïve). The sensitized response seems to be retained about 2 wk and returned to baseline levels by 4 wk.
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To better understand the factors that underlie expression of the sensitized response, characteristics of the strobe stimulus were varied to examine stimulus–response relations in sensitized rats.
EFFECT OF STIMULUS FREQUENCY.
To determine the effect of the temporal frequency of the visual stimulus on response expression, sensitized rats (n = 7) were tested with a range of strobe frequencies (1–30 Hz). As shown (Fig. 9), the amplitude and appearance of the sensitized responses varied with strobe frequency. The initial response to the 1-Hz stimulus has the appearance of a flash-evoked potential with enhanced late components (i.e., flash-evoked after discharge; Bigler 1977). Increases in stimulus frequency led generally to more regular expression of the spike-wave response. When ECoG magnitude was quantified and plotted as a function of frequency of stroboscopic stimulation, the greatest magnitude responses were observed at 4–8 Hz, with a consistent peak at 8 Hz (Fig. 10). A secondary peak occurred near 16 Hz, and a diminution in response was observed at frequencies between the primary and secondary peaks and at the lowest and highest frequencies tested. While 8 Hz was the standard strobe frequency for sensitizing rats, 3-Hz stimulation was used in three rats to test the effect of sensitizing with a different stimulus frequency. There was no difference in the frequency response curve for rats sensitized through exposure to 8-Hz strobe trains or to 3-Hz strobe trains (paired t-test, P > 0.25). Data from both sets of rats were combined in Fig. 10.
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EFFECT OF STIMULUS DURATION. The incidence of occurrence of a spike-wave response was affected little by the duration of the strobe train. A spike-wave response occurred in sensitized rats on 70–80% of trials for virtually every length strobe train (from 4 to 50 strobe flashes per train). Spike-wave incidence (31% of trials) was reduced only when single strobe flashes presented at 1 Hz were used, consistent with the latency results below, because most spike-wave episodes triggered by the fourth strobe flash.
While the incidence of spike-wave episodes remained relatively invariant, the actual duration of a spike-wave episode was related in part to strobe train duration (Fig. 13). For shorter strobe trains, the number of spike-wave discharges rose with increases in the number of flashes in the train (Fig. 13A, left vs. middle column). However, further increases in the strobe train length yielded limited increase in duration of the spike-wave episode (Fig. 13A, middle vs. right column), despite presentation of a strobe frequency (8 Hz) that elicits the strongest response. The longest strobe trains were instead associated with the appearance of multiple, discrete spike-wave episodes (e.g., Fig. 13A, bottom). Quantified data show the spike-wave episode usually exceeded the period of stimulation for the shortest strobe trains (these data points lie above the dashed line in Fig. 13B that indicates correspondence between number of flashes and spike-wave responses). However, for longer strobe trains, the response plateaus maximally around 10–12 spike-wave discharges in length, regardless of the number of flashes per strobe train.
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10 flashes. Third, the response exhibits a limited, but persistent self-sustained character, persisting up to three cycles after termination of the strobe. |
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DISCUSSION |
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The sensitized response exhibited both stimulus-dependent and stimulus-independent features. Longer and more intense visual stimuli were associated with larger, more frequent, and more rapidly triggered spike-wave responses within selected ranges of strobe parameters, and spectral response characteristics reflected the frequency of the photic stimulation. However, the spike-wave response also exhibited characteristics unrelated to the triggering stimulus. Spectral analysis revealed an underlying 6- to 8-Hz rhythm, regardless of the frequency of photic stimulation. The response also exhibited persistence after termination of strobing and yet was ultimately self-limiting in duration regardless of ongoing photic stimulation. Many features of the sensitized response are consistent with properties of the visual thalamocortical pathways. This neural circuitry provides the primary ascending pathway for vision and at the same time is implicated strongly in the generation of the normal oscillations of sleep and pathological spike-wave oscillations of certain generalized epilepsies (Destexhe and Sejnowski 2001; Destexhe et al. 1993, 1999; Sherman and Guillery 2001).
The finding of an inherent 6- to 8-Hz rhythm is consistent with the natural pacing of the rat thalamocortical circuitry, which resonates optimally at 5–10 Hz, even during spike-wave seizures (Destexhe and Sejnowski 2001). This results from hyperpolarization-mediated pacing dominated by GABAA receptors and contrasts with the lower-frequency spike-wave oscillations in primates and cats paced by longer-lasting GABAB-mediated hyperpolarization (Destexhe and Sejnowski 2001; Pinault et al. 1998; Steriade and Contreras 1995; von Krosigk et al. 1993). The observed decline in response at 10 and 13 Hz likely reflects short interflash intervals so that the response to a flash is opposed by deep hyperpolarization from the preceding flash.
The spike-wave response showed both persistence and self-limitation. The response can continue up to three spike-wave cycles after termination of the strobe train, yet, even in the presence of an ongoing strobe stimulus, it ceases after a maximal duration of 10–15 cycles. The visual stimulus plus an inherent self-sustaining mechanism appear to drive the response, while a self-limiting mechanism that may build up over the course of an oscillatory episode terminates the response. Thus qualities of persistence and self-limitation were not mutually exclusive. These results support and extend observations (Jayakar and Chiappa 1990; So et al. 1993) that time of delivery or triggering by a photic stimulus help determine whether a photoparoxysmal response terminates before the end of photic stimulation or persists beyond stimulus termination. Spike-wave episodes that start near termination of the strobe train in the present experiments were more likely to persist beyond strobe termination.
Sensitization reflects long- and short-term change
Our data suggest both long-term and short-term neuroplastic changes occur in thalamocortical circuitry in the adult brain as a consequence of repeated strobe stimulation. First, the sensitized response exhibits long-term plasticity, building up over days and with retention for weeks after the last stimulus exposure. The previously reported flash-evoked afterdischarge (FEAD) that follows the rat visual-evoked occipital response to a single pulse also has some epileptiform features, can evolve over days with extended exposure (Bigler 1977; King et al. 1980), and involves long-term response sensitization (Dyer 1989). This experiment examined responses to trains of strobe stimuli, rather than to isolated flashes, and further showed response retention and generalization. However, the spike-wave responses in this study likely reflect an interaction between afterdischarge processes and the primary visual responses to subsequent strobes in a train, and a similar sensitization process may underlie both the FEAD results and these findings.
The present response features are consistent with long-term potentiation (LTP). LTP occurs in adult thalamo-cortical, cortico-cortical, and cortico-thalamic synapses (e.g., Aizenman et al. 1996; Castro-Alamancos and Calcagnotto 1999; Heynen and Bear 2001). Potentiation at one or more of these synapses could transform circuit dynamics to support the robust, synchronized oscillation of the sensitized spike-wave response. Furthermore, the time scale for retention of the spike-wave response, several weeks, corresponds well to that for maintenance of forms of LTP (Abraham 2003; Malenka and Bear 2004). Thus while other mechanisms may be involved, these results are consistent with features of LTP.
The sensitized response also exhibits short-term enhancement of response over a shorter time scale at the start of a spike-wave episode. The progressive build-up in response to successive flashes early in the strobe train resembles the thalamocortical augmenting response, a rapidly growing enhancement in cortical evoked responses to repetitive electrical stimulation of the thalamus first described by Dempsey and Morison (1943); also see Bazhenov et al. 1998a,b; Castro-Alamancos and Connors 1996a,b,c; Morison and Dempsey 1943; Steriade and Timofeev 1997). The augmenting response is proposed to be involved in the generation of sleep spindles and pathological thalamocortical oscillations. The augmenting response is triggered optimally with 8- to 15-Hz electrical stimulation (Dempsey and Morison 1943) and observed during periods of awake immobility and abolished with states of movement and arousal (Castro-Alamancos and Connors 1996b; Steriade et al. 1969), all of which bears similarity to these results.
The finding that we can induce an augmenting response with visual stimulation is novel; prior studies of thalamocortical augmenting responses failed to produce the response with electrical stimulation peripheral to thalamus (Bazhenov et al. 1998a; Castro-Alamancos and Connors 1996b; Ferster and Lindström 1985). One key difference between those experiments and the present may be choice of stimuli. Natural visual stimulation may be more effective at driving an augmenting response than electrical stimulation of an afferent pathway (e.g., optic tract). In addition, acquisition of a sensitized state may also be relevant. We did not observe augmentation of response in initial trials in naïve animals and also did not observe a fully developed spike-wave response. Only after acquisition of sensitization was an augmenting response observed. Thus the visually-driven augmenting response appears to be a property of the circuit that has undergone induction of the sensitized state.
Similar mechanisms are likely to underlie ECoG response augmentation at onset of a spike-wave episode and the thalamocortical augmenting responses elicited with electrical stimulation (e.g., Bazhenov et al. 1998a,b; Castro-Alamancos and Connors 1996c; Destexhe and Sejnowski 2001; Steriade et al. 1998), in which a key factor is the rebound spike burst in thalamic and cortical neurons from a hyperpolarization that follows an excitatory drive from the stimulus. With appropriate interflash intervals, the rebound burst and excitatory response to a subsequent stimulus coincide, leading to response augmentation. While other explanations exist, a negative potential recorded at the dural surface can reflect a current source in deep cortical layers, so the negative potential that precedes the first spike-wave discharge in this experiment would be consistent with the proposal that hyperpolarization is critically involved in onset of the spike-wave wave episode. Repeated visual stimulation in these experiments or repetitive thalamic stimulation (Steriade et al. 1998) both appear efficacious in producing strong augmenting responses in combination with intact reciprocal pathways between thalamus and cortex. Augmentation is reported at intrathalamic, corticocortical, and corticothalamic connections (Granseth 2004; Granseth and Lindstrom 2004; Houweling et al. 2002; Steriade and Timofeev 1997; Timofeev and Steriade 1998; Timofeev et al. 2002). Augmentive change at any of these sites may potentially contribute to the generation of a sensitized response.
Broader implications
These results are not specific to a particular type of rat. Both sexes and three standard strains of rat acquired the spike-wave response. Prior studies suggest that comparable photic-induced responses may occur in the normal primate brain. These include a strobe-induced, state-dependent spike-wave response (termed "spike and hump") in macaque monkey (Walker et al. 1944) and the proposal that human subjects with no prior evidence of epileptiform activity can show paroxysmal responses after extended stroboscopic stimulation (Brandt et al. 1961). These findings appear distinct from genetic models of photoparoxysmal response and seizure, which can display dissimilar anatomic and electrocorticographic features and need not require sensitization (e.g., Naquet et al. 1995).
The sensitized responses observed in these normal rats share electrographic characteristics with photoparoxysmal responses in humans (e.g., Chatrian et al. 1983; Jayakar and Chiappa 1990; Noachtar et al. 1999; Reilly and Peters 1973). While exhibiting characteristics of photic driving because it is propelled by and reflects the strobe stimulus, the rat response develops additional features not seen in photic driving. Reilly and Peters (1973) described in humans a high-amplitude, visually entrained photoparoxysmal response unlinked to epilepsy that they termed "stimulus-dependent," but this was localized occipitally. Instead, the rat response exhibits electrographic features of the human type 4 photoparoxysmal response, defined as a spike or poly-spike-and-slow-wave response to photic stimulation that generalizes across the brain (Doose and Waltz 1993).
While we did not observe a behavioral correlate to the acquired response, it presents epileptiform electrographic characteristics of photo-triggered synchronization. Its persistence after termination of the strobe stimulation is consistent with a prolonged photoparoxysmal categorization (Reilly and Peters 1973), which is highly correlated with epilepsy in human subjects. Because of this correlation, one might infer that the photoparoxysmal response resulted from abnormal expression in an epileptic brain. In this study, however, the spike-wave response was acquired in normal rats and thus may reflect a normal, albeit extremely sensitized, response. Alternatively, repetitive exposure to intense visual stimuli may induce pathological overexpression of learning-based plasticity processes, resulting in anomalous neural activity that yields the spike-wave response.
Photic-induced sensitization may have greatest impact on individuals with epilepsy. Concern persists that exposure to repetitive photic stimulation from video games, television, and other entertainment-related venues may not only trigger abnormal corticographic responses in vulnerable individuals but may contribute in some manner to development of a vulnerability to triggerability (Appleton et al. 2000; Gastaut et al. 1962; Harding and Jeavons 1994; Singh et al. 2001; Walter and Walter 1949). This raises the question whether neuroplastic changes such as those underlying the present acquisition of sensitization, with heightened propensity for generalized synchrony, could exacerbate expression of photo-triggered seizures in patients with a genetic propensity toward photo-triggered epilepsy. Gastaut et al. (1962) previously raised concern that extended television viewing could "progressively increase brain excitability to such an extent that, after a few hours, stimuli that are otherwise without effect, become at last epileptogenic." Acquisition of the sensitized state in the normal subject could yield benign photoparoxysmal responses, but acquisition of the sensitized state in a seizure-prone subject could lower the threshold for photo-triggered and perhaps primary-generalized seizures. Thus sensitization could, in essence, serve as a mild form of photic kindling or visual priming. Support for this arises from the observation that electrical kindling of the lateral geniculate nucleus in cats administered the convulsant, Metrazol, reduces the threshold for photo-triggered seizures (Wada et al. 1986). Additional support arises from a twin study in which a teenager with frequent exposure to stroboscopic stimulation exhibits far greater photosensitivity than his less photically exposed monozygotic brother (de Haan et al. 2005).
Sensitization through photic exposure appears transitory in our preparation, with rat responses returning to normal after a few weeks once exposure has ceased. Transient sensitivity may be a factor in patients reported to have photo-triggered seizures that were unconfirmed on later clinical examination (e.g., Graf et al. 1994; Ishiguro et al. 2004). These results suggest acquired sensitization could have dissipated in the delay before patients were tested. These results also may provide insight into the shown benefits of abstinence in treating video game epilepsy (De Marco and Ghersini 1985; Graf et al. 1994; Maeda et al. 1990 provide additional references). Abstinence from game-playing and other provocative stimuli may remove patients not only from potential visual triggers of seizure, but also from visual stimuli that contribute to acquisition or maintenance of a sensitized state.
The ordinary neural response to the strobe stimulus has been clearly altered in these experiments. The results provide an example of experience-dependent long-term neuronal plasticity. In the adult visual system, long-term plasticity is associated commonly with perceptual learning (Tsodyks and Gilbert 2004). The strobe stimulation in these experiments could cause either an overexpression of learning-related synaptic plasticity or could bring into play other mechanisms, possibly protective, that modify synaptic strengths. In either case, such synaptic alterations are likely to impact sensory processing and may affect perception. Human patients with photosensitive epilepsy exhibit potentiated visual responses (Hishikawa et al. 1967) and altered visual perception, notably in measures of contrast gain (Porciatti et al. 2000; Wilkins et al. 2004), and the altering effects of repeated peripheral stimulation on somatosensory cellular responses, receptive field size, and perception are well recognized (Klein et al. 2004; Recanzone et al. 1990). Thus the neuroplastic changes observed in this study may have perceptual consequences as well.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. J. Uhlrich., Dept. of Anatomy, Univ. of Wisconsin-Madison, Medical School, 1300 University Ave., Madison, WI 53706-1532 (E-mail: duhlrich{at}wisc.edu)
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REFERENCES |
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|
Aizenman CD, Kirkwood A, and Bear MF. A current source density analysis of evoked responses in slices of adult rat visual cortex: implications for the regulation of long-term potentiation. Cereb Cortex 6: 751–758, 1996.
Appleton R, Beirne M, and Acomb B. Photosensitivity in juvenile myoclonic epilepsy. Seizure 9: 108–111, 2000.[CrossRef][Web of Science][Medline]
Bazhenov M, Timofeev I, Steriade M, and Sejnowski TJ. Cellular and network models for intrathalamic augmenting responses during 10-hz stimulation. J Neurophysiol 79: 2730–2748, 1998a.
Bazhenov M, Timofeev I, Steriade M, and Sejnowski TJ. Computational models of thalamocortical augmenting responses. J Neurosci 18: 6444–6465, 1998b.
Bigler ED. Neurophysiology, neuropharmacology and behavioural relationships of visual system evoked after-discharges: a review. Biobehav Rev 1: 95–112, 1977.
Bland BH The physiology and pharmacology of hippocampal formation theta rhythms. Prog Neurobiol 26: 1–54, 1986.[CrossRef][Web of Science][Medline]
Brandt H, Brandt S, and Vollmond K. EEG response to photic stimulation in 120 normal children. Epilepsia 2: 313–317, 1961.[Web of Science][Medline]
Castro-Alamancos MA and Calcagnotto ME. Presynaptic long-term potentiation in corticothalamic synapses. J Neurosci 19: 9090–9097, 1999.
Castro-Alamancos MA and Connors BW. Cellular mechanisms of the augmenting response: short-term plasticity in a thalamocortical pathway. J Neurosci 16: 7742–7756, 1996a.
Castro-Alamancos MA and Connors BW. Short-term plasticity of a thalamocortical pathway dynamically modulated by behavioral state. Science 272: 274–277, 1996b.[Abstract]
Castro-Alamancos MA and Connors BW. Short-term synaptic enhancement and long-term potentiation in sensory motor cortex. Proc Natl Acad Sci USA 93: 1335–1339, 1996c.
Chatrian GE, Bergamini L, Dondey M, Klass DW, Lennox-Buchthal M, and Petersén I. A glossary of terms most commonly used by clinical electroencephalographers. In: Recommendations for the Practice of Clinical Neurophysiology, edited by Cobb WA. Amsterdam: Elsevier, 1983.
Chuckowree JA, Dickson TC, and Vickers JC. Intrinsic regenerative ability of mature CNS neurons. Neuroscientist 10: 280–285, 2004.
Crunelli V and Leresche N. Block of thalamic T-type Ca2+ channels by ethosuximide is not the whole story. Epilepsy Curr 2: 53–56, 2002.[CrossRef][Medline]
de Haan G-J, Kasteleijn-Nolst Trenité D, Stroink H, Parra J, Voskuyl R, Lindhout D, and Bertram E. Monozygous twin brothers discordant for photosensitive epilepsy: possible environmental influence on the phenotypic expression of a common genotype. Epilepsia 46: 1545–1549, 2005.[CrossRef][Web of Science][Medline]
De Marco P and Ghersini L. Videogames and epilepsy. Dev Med Child Neurol 27: 519–521, 1985.[Web of Science][Medline]
Dempsey EW and Morison RS. The electrical activity of a thalamocortical relay system. Am J Physiol 138: 283–296, 1943.
Destexhe A and Marder E. Plasticity in single neuron and circuit computations. Nature 431: 789–795, 2004.[CrossRef][Medline]
Destexhe A, McCormick DA, and Sejnowski TJ. A model for 8–10 Hz spindling in interconnected thalamic relay and reticularis neurons. Biophys J 65: 2473–2477, 1993.[Web of Science][Medline]
Destexhe A, McCormick DA, and Sejnowski TJ. Thalamic and thalamocortical mechanisms underlying 3hz spike-and-wave discharges. Prog Brain Res 121: 289–307, 1999.[Medline]
Destexhe A and Sejnowski TJ. Thalamocortical assemblies: how ion channels, single neurons and large-scale networks organize sleep oscillations. In: Monographs of the Physiological Society. Oxford: Oxford University Press, 2001, p. 332–343.
Doose H and Waltz ST. Photosensitivity-genetics and clinical significance. Neuropediatrics 24: 249–255, 1993.[Web of Science][Medline]
Dyer RS. Peak N160 of rat flash evoked potential: does it reflect habituation or sensitization? Physiol Behav 45: 355–362, 1989.[CrossRef][Medline]
Ferster D and Lindström S. Augmenting responses evoked in area 17 of the cat by intracortical axonal collaterals of cortico-geniculate cells. J Physiol 367: 217–232, 1985.
Gastaut H, Regis H, and Bostem F. Attacks provoked by television, and their mechanism. Epilepsia 3: 438–445, 1962.[CrossRef][Web of Science]
Graf WD, Chatrian GE, Glass ST, and Knauss TA. Video game-related seizures: a report on 10 patients and a review of the literature. Pediatrics 93: 551–556, 1994.
Granseth B and Lindstrom S. Augmentation of corticogeniculate EPSCs in principal cells of the dorsal lateral geniculate nucleus of the rat investigated in vitro. J Physiol 556: 147–157, 2004.
Granseth B. Dynamic properties of corticogeniculate excitatory transmission in the rat dorsal lateral geniculate nucleus in vitro. J Physiol 556: 135–146, 2004.
Harding GF and Jeavons PM. Photosensitive epilepsy. In: Clinics in Developmental Medicine. No. 133, London: MacKeith Press, 1994.
Heynen AJ and Bear MF. Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo. J Neurosci 21: 9801–9813, 2001.
Hishikawa Y, Yamamoto J, Furuya E, Yamada Y, Miyazaki K, and Kaneko Z. Photosensitive epilepsy: relationships between the visual evoked responses and the epileptiform discharges induced by intermittent photic stimulation. Electroencephalogr Clin Neurophysiol 23: 320–334, 1967.[CrossRef][Web of Science][Medline]
Hodzic A, Veit R, Karim AA, Erb M, and Godde B. Improvement and decline in tactile discrimination behavior after cortical plasticity induced by passive tactile coactivation. J Neurosci 24: 442–446, 2004.
Houweling AR, Bashenov M, Tomofeev I, Grenier F, Steriade M, and Sejnowski TJ. Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex. J Physiol 542: 599–617, 2002.
Ishiguro Y, Takada H, Watanabe K, Okumura A, Aso K, and Ishikawa T. A follow-up survey on seizures induced by animated cartoon TV program "Pocket Monster". Epilepsia 45: 377–383, 2004.[CrossRef][Web of Science][Medline]
Jayakar P and Chiappa KH. Clinical correlations of photoparoxysmal responses. Electroencephalogr Clin Neurophysiol 75: 251–254, 1990.[CrossRef][Web of Science][Medline]
King GA, Burnham WM, and Livingston KE. Flash-evoked afterdischarge in rat as model of the absence seizure: dose-response studies with therapeutic drugs. Epilepsia 21: 531–539, 1980.[Web of Science][Medline]
Klein T, Magerl W, Hopf H-C, Sandkühler J, and Treede R-D. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 24: 964–971, 2004.
Kostopoulos GK. Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis. Clin Neurophysiol 111: 27–38, 2000.[CrossRef]
Leroy C and Roussel A. Systematization of the effects of variations of intensity of intermittent luminous stimulation. 2. Relativity of the intensities of the stimulations as a function of the environment and of the attitude of the subject in relation to it. Rev Neurol (Paris) 105: 190–191, 1961.[Medline]
Maeda Y, Kurokawa T, Sakamoto K, Kitamoto I, Ueda K, and Tashima S. Electroclinical study of video-game epilepsy. Dev Med Child Neurol 32: 493–500, 1990.[Web of Science][Medline]
Malenka RC and Bear MF. LTP and LTD; an embarrassment of riches. Neuron 44: 5–21, 2004.[CrossRef][Web of Science][Medline]
Meeren HKM, Pijn JPM, Van Luijtelaar ELJM, Coenen AML, and Lopes da Silva FH. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 22: 1480–1495, 2002.
Morison RS and Dempsey EW. Mechanism of thalamocortical augmentation and repetition. Am J Physiol 138: 297–308, 1943.
Nagarajan L, Kulkarni A, Palumbo-Clark L, Gregory PB, Walsh PJ, Gubbay SS, Silberstein JM, Silberstein EP, Carty EL, and Dimitroff WR. Photoparoxysmal responses in children: their characteristics and clinical correlates. Pediatr Neurol 29: 222–226, 2003.[CrossRef][Web of Science][Medline]
Naquet R, Silva-Barrat C, and Menini C. Reflex epilepsy in the Papio-papio baboon, particularly photosensitive epilepsy. Ital J Neurol Sci 16: 119–125, 1995.[CrossRef][Web of Science][Medline]
Noachtar S, Binnie C, Ebersole J, Mauguière F, Sakamoto A, and Westmoreland B. A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. In: Recommendations for the Practice of Clinical Neurophysiology: Guidelines of the International Federation of Clinical Neurophysiology, [Electroencephal Clin Neurophysiol Suppl #52], edited by Deuschl G and Eisen A. Amsterdam: Elsevier, 1999.
O'Keefe J and Recce ML. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3: 317–330, 1993.[CrossRef][Web of Science][Medline]
Otsu Y, Kimura F, and Tsumoto T. Hebbian induction of LTP in visual cortex: perforated patch-clamp study in cultured neurons. J Neurophysiol 74: 2437–2444, 1995.
Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates (2nd ed.). Sydney: Academic Press, 1986.
Pinault D, Leresche N, Charpier S, Deniau JM, Marescaux C, Vergnes M, and Crunelli V. Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in rats with absence epilepsy. J Physiol 509: 449–456, 1998.
Poncer JC. Hippocampal long term potentiation: silent synapses and beyond. J Physiol Paris 97: 415–422, 2003.
Porciatti V, Bonanni P, Fiorentini A, and Guerrini R. Lack of cortical contrast gain control in human photosensitive epilepsy. Nat Neurosci 3: 259–263, 2000.[CrossRef][Web of Science][Medline]
Puglia JF, Brenner RP, and Soso MJ. Relationship between prolonged and self-limited photoparoxysmal responses and seizure incidence: study and review. J Clin Neurophysiol 9: 137–144, 1992.[Web of Science][Medline]
Recanzone GH, Allard TT, Jenkins WM, and Merzenich MM. Receptive-field changes induced by peripheral nerve stimulation in SI of adult cats. J Neurophysiol 63: 1213–1225, 1990.
Reilly LR and Peters JF. Relationship of some varieties of electroencephalographic photosensitivity to clinical convulsive disorder. Neurology 23: 1050–1057, 1973.
Riggs LA. Light as a stimulus for vision. In: Vision and Visual Perception. Edited by Graham CL. New York: John Wiley, 1965, p.1–38.
Romanelli P and Esposito V. The functional anatomy of neuropathic pain. Neurosurg Clin N Am 15: 257–268, 2004.[CrossRef][Web of Science][Medline]
Sah DW, Ossipo MH, and Porreca F. Neurotrophic factors as novel therapeutics for neuropathic pain. Nat Rev Drug Discov 2: 460–472, 2003.[CrossRef][Web of Science][Medline]
Salami M, Fathollahi Y, and Motamedi F. Primed-burst potentiation in adult rat visual cortex in vitro. Brain Res Dev Brain Res 118: 93–98, 1999.[CrossRef][Medline]
Seitz AR and Watanabe T. Psychophysics: is subliminal learning really passive? Nature 422: 36, 2003.[CrossRef][Medline]
Sherman SM and Guillery RW. Exploring the Thalamus. London: Academic Press, 2001.
Singh R, Bhalla A, Lehl SS, and Sachdev A. Video game epilepsy. Neurol India 49: 411–412, 2001.[Web of Science][Medline]
Skaggs WE, McNaughton BL, Wilson MA, and Barnes CA. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6: 149–172, 1996.[CrossRef][Web of Science][Medline]
Snead OC Pharmacological models of generalized absence seizures in rodents. J Neural Transm Suppl 35: 7–19, 1992.[Medline]
So EL, Ruggles KH, Ahmann PA, and Olson KA. Prognosis of photoparoxysmal response in nonepileptic patients. Neurology 43: 1719–1722.
Steriade M and Amzica F. Sleep oscillations developing into seizures in corticothalamic systems. Epilepsia 44: 9–20, 2003.
Steriade M and Contreras D Relations between cortical and thalamic cellular events during transition from sleep patterns to paroxysmal activity. J Neurosci 15: 623–642, 1995.[Abstract]
Steriade M, Iosif G, and Apostol V. Responsiveness of thalamic and cortical motor relays during arousal and various stages of sleep. J Neurophysiol 32: 251–265, 1969.
Steriade M, Nunez A, and Amzica F. Intracellular analysis of relations between the slow (< 1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J Neurosci 13: 3266–3283, 1993.[Abstract]
Steriade M and Timofeev II. Short-term plasticity during intrathalamic augmenting responses in decorticated cats. J Neurosci 17: 3778–3795, 1997.
Steriade M, Timofeev I, Grenier F, and Dürmüller N. Role of thalamic and cortical neurons in augmenting responses and self-sustained activity: dual intracellular recordings in vivo. J Neurosci 18: 6425–6443, 1998.
Timofeev I, Bazhenov M, Sejnowski T, and Steriade M. Cortical hyperpolarization-activated depolarizing current takes part in the generation of focal paroxysmal activities. Proc Natl Acad Sci USA 99: 9533–9537, 2002.
Timofeev I and Steriade M. Cellular mechanisms underlying intrathalamic augmenting responses of reticular and relay neurons. J Neurophysiol 79: 2716–2729, 1998.
Tsodyks M and Gilbert C. Neural networks and perceptual learning. Nature 431: 775–781, 2004.[CrossRef][Medline]
von Krosigk M, Bal T, and McCormick DA. Cellular mechanisms of a synchronized oscillation in the thalamus. Science 261: 361–364, 1993.
Wada Y, Minabe Y, Okuda H, Jibiki I, Yoshida K, and Yamaguchi N. Lateral geniculate kindling and long-lasting photosensitivity in cats. Exp Neurol 91: 343–354, 1986.[CrossRef][Web of Science][Medline]
Walker AE, Woolf JI, Halstead WC, and Case TJ. Photic driving. Arch Neurol Psychiatry 52: 117–125, 1944.
Walter VJ and Walter WG. The central effects of rhythmic sensory stimulation. Electroencephalogr Clin Neurophysiol 1: 57–86, 1949.
Watanabe T, Nanez JE, and Sasaki Y. Perceptual learning without perception. Nature 413: 844–848, 2001.[CrossRef][Medline]
Wilkins AJ, Bonanni P, Porciatti V, and Guerrini R. Physiology of human photosensitivity. Epilepsia 45: 7–13, 2004.
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ABSTRACT
INTRODUCTION
