Excitability changes at brainstem and cortical levels in blind subjects

Clinical Neurophysiology 122 (2011) 1827–1833

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Excitability changes at brainstem and cortical levels in blind subjects q Elif Kocasoy Orhan a,⇑, Vildan Yayla b, Zafer Cebeci c, M. Barısß Baslo a, Tunç Ovalı c, A. Emre Öge a a

Department of Neurology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey Department of Neurology, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey c Department of Ophthalmology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey b

a r t i c l e

i n f o

Article history: Accepted 14 February 2011 Available online 31 March 2011 Keywords: Blind subjects Brainstem Blink reflex Blink reflex recovery Cortical excitability Paired TMS Facial F Conditioning Extinction

h i g h l i g h t s  Blink reflex recovery is reduced in blind subjects and restores with continuation of the stimulation.  In blind subjects, TMS studies reveal reduced intracortical inhibition and facial F waves suggest the presence of possible influence of this altered cortical excitability on facial motor nuclei.  Firing probabilities of facial motor neurons in blind subjects are probably determined by the equilibrium between the low-set excitability of blink reflex interneurons and the enhanced excitability brought on by the descending motor pathways.

a b s t r a c t Objectives: This study was designed to search potential changes in trigemino-facial system in blind subjects by the use of relatively well-established electrophysiological methods. Excitability changes in the motor cortex were also investigated by transcranial magnetic stimulation studies (TMS) with the expectation of finding some abnormal interactions between the cortex and brainstem. Methods: Twenty blind (BS) and 13 control subjects (CoS) were included in the study. Blink reflex and its recovery with paired electrical stimulation were studied at 150, 200, 300, 400 and 500 ms interstimulus intervals (ISI). Facial F waves elicited by buccal branch stimulation were recorded from nasalis muscles. Motor cortex excitability with recordings from left first dorsal interosseus muscle was studied by using magnetically elicited silent periods and paired magnetic stimuli, subthreshold conditioning and suprathreshold test, given at ISIs of 2, 3, 4, 10, 12, 15 and 20 ms. Results: Blink reflex recovery was significantly reduced in BS group comparing to CoS at 400 and 500 ms ISIs. This difference between the groups was more prominent for the responses evoked by the initial stimulation side and faded away with stimulations on the contralateral side. Facial F wave amplitudes and F/ M amplitude ratios were higher in BS group. In TMS studies, the early inhibitions at 2 and 4 ms were found to be significantly less in BS as compared to that of CoS. Conclusions: The reduced blink reflex recovery and its fast restoration with continuing stimulation might be explained by conditioning and extinction processes which have been shown to be mainly carried out by cerebellar–brainstem pathways. Our TMS studies showed reduced intracortical inhibition in the motor cortices of BS cases and facial F wave studies revealed the possible effect of this altered excitability on the facial motor nuclei. Significance: Firing probabilities of facial motor neurons in BS are probably determined by the equilibrium between the low-set excitability of blink reflex interneurons and the enhanced excitability brought on by the descending motor pathways. Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction q Presented as a poster at the 13th European Congress of Clinical Neurophysiology, Istanbul 2008. _ _ ⇑ Corresponding author. Address: Istanbul Üniversitesi, Istanbul Tıp Fakültesi, _ Nöroloji Anabilim Dalı, 34390 Istanbul, Turkey. Tel.: +90 212 4142000; fax: +90 212 5334393. E-mail address: [email protected] (E.K. Orhan).

Short- and long-term plastic reorganizations in the representations of different sensory modalities in the brain occur following loss of inputs into one of these sensations. Hearing and sound localization have been shown to be better in blinds than in sighted subjects (Chen et al., 2002). In patients with the loss of a particular

1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2011.02.020

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sensory modality since birth, the deprived cortex can be recruited by other sensory modalities, supporting the concept of crossmodal plasticity. This well-described phenomenon may underlie enhanced tactile and auditory skills in blind subjects (Rauschecker et al., 1992; Wittenberg et al., 2004). Although, most of the evidence points to the cortical level as the theatre of these plastic changes, subcortical structures such as thalamus, brainstem and spinal cord were also claimed to be involved in these reorganizational processes (Chen et al., 2002). In contrast to the presence of several electrophysiological studies showing the transmodal cortical plasticity in blind subjects, possible functional reorganization at the brainstem level have not been studied in detail. In this study, we aimed to evaluate possible excitability changes in blind subjects both at the brainstem and cortical levels by use of relatively well established electrophysiological methods.

2. Methods 2.1. Cases Electrophysiological tests were performed in 20 subjects (4 females and 16 males, aged between 22 and 51 years) having either congenital or acquired blindness (blind subjects = BS) (Supplementary Table S1). Six patients had loss of vision since birth or early childhood (62 years), whereas 14 patients became afflicted with vision loss in later years. Ophthalmological examination performed at the time of electrophysiological studies suggested that the causes of vision loss were retinitis pigmentosa (5 patients), congenital cataracts and/or glaucoma (8 patients), infection (4 patients), trauma (2 patients) and Behcet’s disease (1 patient). While 13 patients had total vision loss with no sense of light, the remaining 7 patients had severe bilateral partial visual disturbances with quite symmetrical (2 patients) or asymmetrical (5 patients) perception of light and/or hand movement in close distance. Seventeen patients had the ability of Braille reading and using special electronic devices for the blind (cell phone and computers). All of the cases in BS group were right-handed except three who were ambidextrous exclusively in reading Braille with either right or left hand preference. Control values were obtained from 12 (6 females and 6 males) healthy members of our institution volunteered for the study (CoS group) whose ages ranged between 25 and 43 years. Neurological examination was normal in all cases and none of them had taken any drug with depressing and stimulating effects on the central nervous system at least during the week before the day of electrophysiological studies, except three BS cases who were excluded from TMS studies due to anticonvulsive medication. Informed consent was obtained from each subject and the local ethics committee approved the study.

3. Electrophysiological methods Electrophysiological studies in each patient were performed in a single afternoon session and in the same order of examinations (unless otherwise indicated) as presented below. Since all stimulation and recordings were performed in accordance with the methods described elsewhere, they will be presented in concise form herein (Öge et al., 2005; Yayla et al., 2008). 3.1. Blink reflex and its recovery A Medelec Synergy electromyography instrument was used for blink reflex and facial F wave studies.

Active surface electrodes were placed on midpoints of both inferior orbicularis oculi muscles (Ooc) of the cases lying supine on a coach who were instructed to keep their eyes open except for their natural blinking. The minimum current level of single electrical stimulus producing a consistent 50 lV R2 response was defined as the R2 threshold intensity. Constant current paired stimuli of 0.1 ms duration at three times the R2 threshold intensity were delivered to the right and left supraorbital nerve at interstimulus intervals (ISI) of 150, 200, 300, 400 and 500 ms (in the same order from the shortest to the longest ISI). Four pairs of stimuli for each ISI were applied and recorded traces were stored for offline analysis. To prevent habituation of the reflex, 20–30 s of rest was allowed between the stimulations. The initial stimulation side was not randomized in the case groups. Paired stimuli with all ISIs were given to the right and then to the left supraorbital nerves in the first examined nine patients. After observing the differences between the first and second stimulated sides in an interim analysis which will be presented below, the initial stimulation side in the following 11 patients was changed into the left. On each pair of nonrectified traces, the following parameters of the responses were measured and mean values of the four recordings for each ISI were calculated: Latencies and peak-to-peak amplitudes of R1 responses evoked by the first and second stimulation (1R1 and 2R1, respectively), latencies, amplitudes (from highest negative peak to the deepest positive) and durations (from the first deflection from baseline to the final return) of R2 responses to the first and second stimulation (1R2 and 2R2, respectively). R2 responses recorded from contralateral Ooc muscles were named as 1R2c and 2R2c. Blink reflex recovery calculations were based primarily on the R2 responses (2R2/1R2 and 2R2c/ 1R2c) because of their greater suppression following the conditioning stimuli (Kimura, 2001). R2 recovery values of the CoS group were found to be similar on both sides and pooled for comparison with those of the BS group. 3.2. Facial F-waves Active surface disc electrodes were placed on both nasalis muscles and the reference electrode was applied on the tip of the nose (Öge et al., 2005; Wedekind et al., 2001). Constant current stimuli of 0.1 ms duration at just supramaximal intensity were applied to the buccal branch of facial nerve. Twenty stimuli were applied to each side and recordings were made with 30–50 ms sweep speed and 200–500 lV sensitivity. Peak-to-peak amplitudes of the M and F waves were calculated on each side. Amplitudes of the traces with unobtainable F-waves were accepted as zero and mean amplitude or duration values were calculated by dividing their sum to number of stimuli (n = 20). 3.3. Transcranial magnetic stimulation studies Magnetic stimulation studies were not performed in 2 BS cases with the personal history of epilepsy, 1 BS with suspected seizure and 1 CoS who refused to attend this part of the examination. A Medelec MS25 plus (Mystro) electromyograph and two Magstim 200 magnetic stimulators connected with a Bistim module were used in the magnetic stimulation studies. Electrophysiological recordings were made with surface electrodes placed on the left first dorsal interosseus (FDI) muscle. After positioning the figure-of-eight magnetic coil tangentially over the motor cortex with the handle pointing to the postero-lateral direction, 45° away from the midline, the point at which the TMS could produce the highest amplitude motor responses was determined. The reason of choosing the right hemisphere in our two case groups which were comprised of almost completely right handed persons, was

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to avoid from the possible effects of hand dominance which could be different in BS and CoS groups due to Braille reading in the former.

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3.3.1. Motor thresholds Active motor threshold (AMT) was defined as the stimulation intensity producing motor responses more than 100 lV in

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Fig. 1. Blink reflex recovery curves in blind subjects as compared to the pooled values of controls. BS and CoS groups are shown with black and grey lines, respectively. (A) Right-sided stimulation and recording (RR) in the whole group. (B) Left-sided stimulation and recording (LL) in the whole group. (C) RR stimulation and recording in the first 9 BS cases in whom right side was stimulated first. (D) LL stimulation and recording in the first 9 BS cases (right side stimulated first). Please note the loss of significant differences between the groups. (E) RR stimulation and recording in the second subgroup of 11 BS cases (Left side stimulated first). Recovery curves are nearly identical. (F) LL stimulation and recording in the second subgroup of 11 BS cases (Left side stimulated first). (G) Pooled values of first stimulated sides (RR in the first 9 and LL in the second 11) in BS group as compared to CoS. (H) Pooled values of the second stimulated sides (LL in the first 9 and RR in the second 11) in BS group as compared to CoS. No intergroup difference was found. Statistically significant differences between the groups are marked with asterixis, qP < 0.05, wP < 0.01.

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Table 1 F-waves in blind and control groups.

Persistence M F F/M

BS right

BS left

CoS right

CoS left

P (R)

P (L)

P (Pool)

76.3 ± 30.6% 2142 ± 1119 99.8 ± 84.1 0.06 ± 0.05

81.5 ± 33.2% 2250 ± 1042 127.4 ± 65 0.07 ± 0.05

86.2 ± 22.4% 2683 ± 945 63.5 ± 38 0.03 ± 0.03

88.5 ± 27.1% 2308 ± 1040 60.2 ± 30.1 0.03 ± 0.02

NS NS NS <0.05

NS NS <0.01 <0.01

NS NS <0.01 <0.001

BS: blind subjects, CoS: control subjects, F: F wave amplitude (lV), M: compound muscle action potential amplitude (lV), NS: non-significant, Persistance: F wave persistance (%).

Table 2 Motor thresholds and cortical silent periods in two groups.

BS CoS

SP

AMT

RMT

132.1 ± 33.4 120.6 ± 27.7

41.3 ± 9.8 37.4 ± 5.8

55.6 ± 12.1 55.6 ± 13.6

AMT: active motor threshold, RMT: resting motor threshold, SP: silent period. The other abbreviations are the same as those of Table 1.

amplitude in at least 5 out of the 10 successive trials while the subject was contracting the target muscle isometrically at nearly 20% of the maximal strength which was monitored on the EMG screen (Rossini et al., 1994). Resting motor threshold (RMT) was determined as the stimulation intensity which elicited more than 50 lV motor responses in at least 5 out of the 10 recordings, while the same muscle was in complete relaxation. 3.3.2. Cortical silent period (SP) TMS-induced silent periods were studied during moderate voluntary contraction of the target muscle by single pulses with an intensity of 140% AMT which produced MEPs of 0.54 ± 0.34 mV in our cases. Twelve rectified traces were recorded and SP duration in each trace was measured from the time of the stimulation to the reappearance of the voluntary muscle activity and the mean value of the recordings was calculated. 3.3.3. Cortical excitability with paired TMS paradigm Short interstimulus interval (ISI) intracortical inhibition (SICI) and intracortical facilitation (ICF) were studied as described by Kujirai et al. (1993). During complete relaxation of the target muscle, TMS intensities of 70% RMT and 140% RMT were applied as the subthreshold conditioning and suprathreshold test stimuli, respectively. Paired stimuli with the ISIs of 2, 3, 4, 10, 12, 15 and 20 ms were delivered in a randomized order. A total of 64 recordings [8 paired stimuli for each ISI and 8 single test stimuli (140% RMT)] were made with 100 ms sweep speed and 0.2–2 mV/division sensitivity. The ratios of the mean peak to peak amplitudes and areas of the eight motor responses obtained by test stimuli at each ISI, to those of eight motor responses elicited by single test stimuli were calculated to draw the graphics delineating the courses of SICI and ICF. The ratios calculated at ISIs 2, 3, 4 and ISIs 10, 12, 15 were pooled to represent the SICI and ICF periods, respectively, and these pooled values were used to investigate a correlation between paired TMS results and facial F wave parameters in both groups.

subgroups of BS cases (total vs. severe partial vision loss and congenital vs. acquired blindness) and CoS group. The correlation between the results of F wave and paired TMS studies were analyzed with Spearman’s correlation. MedCalc Version 11.2.1.0 was used for statistical analysis. Values were given as means ± SD. Results were considered significant at the level of p 6 0.05.

4. Results 4.1. Blink reflex and blink reflex recovery studies There was no significant difference between the groups regarding the amplitude and duration of R1, R2 and R2c responses on the right and left sides. The results of blink reflex recovery studies are shown in Supplementary Table S2. Since intergroup differences were similar both for amplitude and duration values (Supplementary Table S2), only those related to the amplitudes are summarized below. The recoveries of R2 and R2c responses were found to be diminished in BS as compared to CoS group, especially at 400 and 500 ms ISIs (Fig. 1A and B). This reduced recovery was particularly noticed in R2 components which were elicited in response to initially stimulated side. The first 9 patients in whom right supraorbital nerves were stimulated initially yielded more marked recovery failure both for R2 and R2c with right side stimulation (Fig. 1C and D). Changing the stimulation order for the following 11 patients as being the left side stimulated first showed insufficient recovery of R2 responses as well, however, this time in response to left supraorbital nerve stimulation (Fig. 1E and F). Lastly, the results for the first and the second stimulation sides pooled for the whole 20 patients. This gave a significantly reduced recovery at ISIs between 300–500 ms in responses elicited by the initial stimulation side and a recovery pattern nearly similar as that of control subjects in those evoked by the later stimulated supraorbital nerve (Fig. 1G and H). 4.2. Facial F-waves F wave persistences were found to be similar on both sides of the BS and CoS groups (Table 1). The amplitudes of facial M responses were also similar on both sides of the two groups; whereas, the amplitudes of F responses and F/M amplitude ratios were significantly higher in the BS group (p < 0.05).

3.4. Statistical analysis

4.3. Magnetic stimulation studies

Blink reflex, F wave, motor threshold and cortical SP findings of BS and CoS groups were compared with using non-parametric two independent sample comparison tests (Mann–Whitney). Blink reflex recovery and paired TMS data of BS and CoS groups were analyzed with non-parametric multiple comparison tests (Kruskall–Wallis). If this revealed significant differences, groups were compared with Mann–Whitney. Similar multiple and two sample comparison tests were used for comparing the findings in

There were no significant difference between the RMT, AMT and CSP values in the two groups (Table 2). In paired TMS studies, motor responses evoked by the test stimuli showed an inhibition at ISI 2, 3, 4 ms, and facilitation at ISI 10–20 ms in both groups. However, in the BS group, the early inhibition at ISI 2 ms (both in amplitudes and areas) and 4 ms (in amplitudes) were found to be significantly less comparing to that of control subjects (Fig. 2).

E.K. Orhan et al. / Clinical Neurophysiology 122 (2011) 1827–1833

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Fig. 2. Paired TMS studies in blind and control subjects. The ratios of peak to peak amplitudes (A) and areas (B) of the motor responses elicited at 2, 3, 4, 10, 12, 15 and 20 ms ISIs to those evoked by single test stimuli are presented. BS and CoS groups are shown with black and grey lines, respectively.

Correlation analyses between the F-wave parameters and paired TMS results in the two case groups gave only a mild correlation between F/M amplitude and paired TMS results in the SICI period in BS cases (rs = 0.34, p = 0.05). 4.4. Findings in different groups of BS There were no significant differences in blink reflex recovery, F wave and TMS results between total and severe partial vision loss groups and between the subgroups with congenital or acquired blindness. Therefore, values of the whole group were exclusively given in detail and made the subject of our discussion. However, reduced blink reflex recovery in BS cases with total vision loss (p < 0.05) as well as reduced blink recovery (p 6 0.01), increased F and F/M amplitudes (p 6 0.01 and p < 0.001, respectively) and reduced inhibition at SICI in paired TMS (p < 0.05) in patients with acquired blindness were found to be significantly different as compared to CoS group. There were no such differences between CoS and BS cases with partial deficit with respect to blink reflex recovery and between CoS and congenitally blind cases concerning blink reflex, F wave and TMS values. Since it is possible that this difference between the subgroups could be caused by low number of cases they had, it will not be discussed further on. 5. Discussion There is a great body of evidence about the development of functional reorganization in cortical areas, both visual and non-visual, in blind subjects (Cohen et al., 1997; Collignon et al., 2009). However, reports on possible functional changes at the brainstem level are very rare in the literature (Sanabria-Bohórquez et al., 2001; Seemungal et al., 2007), and trigemino-facial reflexes in blind persons have not been reported so far. The fate of these reflexes in people devoid of vision for a long time would be a subject of curiosity when their role in the protection of eye and sight is taken into account. This study was planned to search potential changes in trigemino-facial system in blind subjects by the use of relatively well established electrophysiological methods. We also investigated excitability changes in the motor cortex with the expectation of finding some deviant interactions between the cortex and brainstem. The blink reflex, its recovery and facial F waves are leading electrophysiological methods in order to study the excitability status of facial nuclei and trigemino-facial pathways (Valls-Sole˙ et al., 1989; Öge et al., 2005). Our main finding in blink reflex recovery studies in BS was the reduced recovery between 300–500 ms ISI, which was mainly encountered when the responses to the initially stimulated supraorbital nerve were evaluated. This difference between

the BS and CoS groups, which was lost by continuation of the experiment with changing the stimulation side, persisted irrespective of the side (right or left) of initial stimulation. This finding led us to speculate that in a population with long periods of vision loss, the excitability of blink-reflex pathways are reduced possibly because of the insignificance of avoidance reflexes aiming to protect the non-functional eyes. However, it is difficult to explain the mechanisms leading to this reduced level of excitability in blink-reflex interneuronal system in BS and its very fast restoration towards the levels of normals with continued stimulations (Valls-Sole˙ et al., 1989, 2003). One candidate hypothesis to explain this might be created by using the concepts of conditioning and extinction which have been largely discussed in the literature related to experiments on learning and memory. In Pavlovian or ‘‘classical’’ eye blink conditioning, a neutral ‘‘conditioned’’ stimulus (CS) is followed by a blink-eliciting, unconditioned stimulus (US). With repeated CS–US presentations, the CS gradually acquires the ability to elicit a conditioned blink response (CR) (Kandel et al., 2000; Jirenhed et al., 2007; Robleto et al., 2004). Extinction, on the other hand, is evidenced by a decrease in the frequency of the CR due to the repeated presentation of the CS in the absence of the US (Robleto et al., 2004). According to the contemporary view, an organism learns that a CS no longer predicts the US by extinction which is not the destruction or fading away of memory but new learning that interferes with the performance (Kandel et al., 2000; Robleto et al., 2004). Originally learned associations are retained during extinction and they can be recovered rapidly upon testing the CS in a context other than the one in which extinction has occurred (Bouton, 2002; Bouton and Moody, 2004; Robleto et al., 2004, 2008). In several experimental studies cerebellar structures have been shown to have a major role in these processes (Jirenhed et al., 2007; Robleto et al., 2004, 2008; Thompson and Steinmetz, 2009; Weeks et al., 2007). By considering the close liaison between the vision and trigeminal senses and their shared duty as afferents in defending mechanisms against the threats towards the face and eyes, we might assume trigeminal and visual sensory inputs as CS, and US, respectively (Amini et al., 2006). Hence, we can hypothesize that long duration loss of vision (US) could produce an inhibitory effect on the reactions to ongoing trigeminal inputs (CS) by a mechanism similar to the extinction. This might be the cause of the hypoexcitability in blink reflex pathways which was recorded in our BS group as reduced recovery. Its rapid restoration, reflected by our recordings after reversing the stimulation side, can also be explained by recovery of the extincted responses due to the change in the context of extinction by repeated electrical stimuli to the supraorbital region. The speed of this restoration (minutes in our cases) which seems to be somewhat surprising, was within the

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range of those found in animal studies (Jirenhed et al., 2007). Although these mechanisms seem difficult to affect the parameters of classical eye-blink reflex, it is not implausible for them, with their close cerebellar–brainstem interactions, to have an excitatory or inhibitory influence on the brainstem interneuronal system which has a major role in the regulation of blink reflex recovery (Thompson and Steinmetz, 2009; Valls-Solé et al., 1989, 2003). If the order of ISIs and initial stimulation sides in blink reflex recovery studies had been randomized in this study, it might have been possible to show the restoration of reduced recovery even on the initial stimulation side and to avoid from the potential effects of subjects’ anticipation for the second stimulus especially at long ISIs. However, since the reduced recovery of blink reflex was found merely after arriving longer interstimulus intervals, its restoration would have been difficult to be noticed amongst the findings elicited with randomized ISIs. This could have been possible only with a foresight about the presence of this restoration and by analysis of the findings at each ISI recorded with higher number of stimulations in a larger group of cases. Therefore, we think that the lack of randomization of ISIs was probably the cause of our incidental observation on the restoration of reduced blink reflex recovery instead of being a disadvantage in this study. F wave amplitudes and F/M ratios found in our BS cases suggested that their facial motor nuclei were also in a hyperexcitable state (Fisher, 1988, 2002; Öge et al., 2005). Since all of the F wave studies were performed after blink reflex recordings, with intervals lasting a few minutes for relocation of the recording electrodes, recovery of the trigemino-facial reflex pathways through the aforementioned mechanisms can be thought to be operative also in this stage of the study. The reason why high amplitude F waves were not accompanied by exaggerated blink reflex R1 responses can be questioned when considering the oligosynaptic nature of the latter. This difference might be proposed to be caused by the plausibly lower perception thresholds in BS cases to supraorbital stimuli and could have been eliminated by determining the stimulus intensity based on the perceptional threshold rather than based on R2 threshold. However, this suggestion does not seem likely since, by using the same reasoning, stimuli adjusted in this way as the multiplies of perception thresholds would be lower in BS group possibly leading to smaller blink responses and to the enhancement of the discrepancy between them and the F wave results. Although we think that this discrepancy was most likely caused by the order of the studies, F waves following the blink reflex examinations, it is difficult to discriminate whether there was also a role of the resistant character of R1 to suprasegmental influences (Cruccu and Deuschl, 2000). On the other hand, it is difficult to explain the adjustment of facial motoneuron excitability to a level higher than that of controls, which came out with high amplitude F waves, by the recovery of extinction. One alternative explanation could be the possible exaggeration of ‘startle’ reaction in BS in response to facial nerve electrical stimulation for F waves, which might have carried the motoneurons to a higher level of excitability. This seems to be unlikely because, although darkness facilitates acoustic startle in humans, startle reactions of blind subjects were shown not to be higher than those of controls (Bachar et al., 1993; Grillon and Davis, 1997). Moreover, blink reflex components in our BS cases were not enhanced even though eye blink is known as the most persistent component of the startle reflex (Grillon and Davis, 1997). Therefore, we were compelled to look for an explanation coming from supranuclear control of the facial motoneurons since several electrophysiological studies have shown the presence of a substantial descending influence from the motor cortex onto the excitability of brainstem mechanisms (Berardelli et al., 1983; De Vito et al., 2009; Leis et al., 1993).

Numerous studies have shown the presence of cross modal plastic changes between sensory modalities in blind subjects, particularly in those who had lost their vision in early life (Cohen et al., 1997; Sadato et al., 2002; Sathian and Zangaladze, 2002; Gizewski et al., 2003; Sadato, 2005; Kupers et al., 2007; Hötting and Röder, 2009). These changes, with the pivotal role of occipital cortex in their execution, probably provide the superior performance of blinds in the tasks requiring the use of senses other than vision and help them to cope with the difficulties caused by their disability (Hötting and Röder, 2009). Nevertheless, reports regarding the condition of motor cortex in blinds are rarer. Pascual–Leone et al. found that cortical representation of the reading finger in proficient Braille readers is enlarged at the expense of the representation of other fingers (Pascual and Torres, 1993; Pascual et al., 1993). Movements related brain activity preceding voluntary movements was shown to be enhanced in early blinds (Lehtokoski et al., 1998). In a single and paired pulse TMS study, LeonSarmiento et al. showed significantly larger motor-evoked potentials and less intracortical inhibition in visually deprived subjects (Leon Sermiento et al., 2005). These findings verify that visual deprivation increases the excitability of motor cortex just as the visual cortex hyperexcitabiliy it causes (Leon Sermiento et al., 2005; Pitskel et al., 2007). Our paired pulse TMS study in BS group gave reduced intracortical inhibition (ICI) values as compared to those of CoS, a finding that was in concordance with the results of Leon Sermiento et al. This might be interpreted as an increased excitability or reduced inhibition capacity in the motor cortex which is probably useful for BS for facilitating the motor responses performed in a proficiency task or acted in response to incoming signals from the environment. The enhanced excitability of the facial nuclei found in our F wave studies can also be presumed to be generated under the influence of hyperexcitable motor cortex. Therefore, we may think that facial motor innervations in blind subjects are under two opposite effects. Firing probabilities of facial motor neurons are probably determined by the equilibrium between the low-set excitability of blink reflex interneurons and the enhanced excitability brought on by the descending motor pathways. High amplitude F waves in our study could be the result of elimination of one component of this equilibrium by the extinction of low adjusted blink reflex recovery. Acknowledgement The work was supported by the Research Fund of Istanbul University. Project # 462/27122005. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.clinph.2011.02.020. References Amini A, Digre K, Couldwell WT. Photophobia in a blind patient: an alternate visual pathway. Case report J Neurosurg 2006;105:765–8. Bachar E, Peri T, Halamish R, Shalev AY. Auditory startle response in blind subjects. Percept Mot Skills 1993;76:1251–6. Berardelli A, Accornero N, Cruccu G, Fabiano F, Guerrisi V, Manfredi M. The orbicularis oculi response after hemispheral damage. J Neurol Neurosurg Psychiatry 1983;46:837–43. Bouton ME. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol Psychiatry 2002;52:976–86. Bouton ME, Moody EW. Memory processes in classical conditioning. Neurosci Biobehav Rev 2004;28:663–74. Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience 2002;111:761–73. Cohen LG, Celnik P, Pascual-Leone A, Corwell B, Falz L, Dambrosia J, et al. Functional relevance of cross-modal plasticity in blind humans. Nature 1997;389:180–3.

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