Background: Schiffer et al have reported that left and right lateral visual-field stimulation can often evoke different (positive versus negative) psychologic responses in a given patient. Some had improvements while looking to the left and others while looking to the right.
Methods: We asked 37 patients who were severely depressed and resistant to treatment (26 women, 11 men) to report changes in affective state in response to two pairs of goggles, each allowing vision out of either the left or right visual field. We then evaluated whether these responses predicted clinical responses to TMS as measured by the percent decrease in the Hamilton Depression Rating Scale (HDRS.4%) scores between baseline and 4 weeks (2 weeks after a 2-week course of daily TMS).
Results: The 20 patients who felt more improvement with right than left lateral visual-field stimulation with 45-second baseline goggle trials had a 42% (炳 SD 22.2) reduction in HSDR.4%. The 15 patients who felt more improvement looking to the left than to the right had an 11% (炳 SD 28.4) decrease in HSDR.4%. Seventy-five percent of the 20 patients in the first group had a decrease in HSDR.4% more than 20%, and 80% of the 15 in the second group had a decrease in this score of less than 20%. A two-tailed Fisher exact test showed a significant difference between the two groups (p = 0.002).
Conclusion: Baseline affective responses to lateral visual-field stimulation predicted clinical responses to left, frontal TMS in depressed patients.
The mechanisms of action of TMS in the human brain are unclear at cellular level and vague at network level (4 ). One notion regarding the mechanisms of the TMS-induced antidepressant effects in medication refractory depression proposes that TMS might modulate (and thus ??xternally normalize?? the activity in the targeted cortical region (1 ,2 ). Schiffer (11 ) has hypothesized that affective responses to lateral visual-field stimulation might predict clinical responses to TMS. The mechanisms of action of lateral visual-field stimulation are thought to involve the relative activation of the contralateral hemisphere (12 ,13 ), but are not proven. However, any method for predicting responses to TMS could be enormously valuable for optimizing and understanding this experimental modality. Attempts to accomplish this goal by combining TMS and functional imaging are underway (2 ,14 ). Recently, Eschweiler et al (15 ) found that decreased, right, frontal, cortical blood flow on near infrared spectroscopy during a cognitive task predicted clinical responses to TMS. Nevertheless, behavioral measures, such as lateral visual-field stimulation, might be alternative, clinically applicable tools.
Schiffer reported (16 ) that 60% of 70 consecutive psychotherapy patients reported at least a 20% difference in anxiety between left-and right-sided lateral visual-field stimulation by safety goggles taped to allow vision out of only the extreme left or right side, as shown in Figure 1A . The hypothesis that all responsive patients would experience more anxiety when looking to the left visual field (LVF), expected to preferentially stimulate the right hemisphere, was disproved. For example, of 21 patients with major depression, 11 reported greater anxiety when looking to the LVF, but 4 reported more distress when looking to the right visual field (RVF), and 6 reported no difference. The lateralized experimental goggles have been compared with monocular (placebo) goggles, designed to appear complex, as shown in Figure 1B ; this comparison enables experiments to test for the effects of suggestion. The experimental goggles, but not the monocular controls, altered lateral mean frontal and temporal theta electroencephalogram results ( 12 ), and in two trials, the lateralized experimental goggles were found to significantly induce more change than the monocular goggles ( 12 ,16 ). The theta-electroencephalogram findings were very similar to those of Levick etal (17 ) who used lateralized contact lenses to demonstrate contralateral hemispheric activation with lateral visual-field stimulation.
FIG. 1. A: Experimental goggle allowing vision primarily out of the right visual field. B: Left-sided monocular goggle with tape on the bottom of the left lens to give the goggle a more complex appearance.
The hypothesized mechanism for the effects of lateral visual-field stimulation has been reviewed in detail elsewhere (11 ,13 ,16 ). It is based largely on Kinsbourne's hypothesis (18 ) that sensory stimuli to one side of the body tend to activate the contralateral cerebral hemisphere and inhibit the ipsilateral. Sensory stimulation is directed primarily to one hemisphere, but is not limited to that hemisphere. For example, Lempert and Kinsbourne (19 ) reported that college students could perform a verbal task better when looking to the right than when looking to the left, and Schiff et al ( 20 ) report shifts in hemispheric activation with behavioral consequences with unilateral muscle contractions.
For the current study, we hypothesized that patients who felt a decrease in depression when looking to the RVF (thought to activate the left hemisphere) might be more apt to benefit from TMS applied to the left hemisphere at a frequency (10 Hz) intended to activate that hemisphere. With similar logic, we expected patients who felt an intensification of their depression when looking to that side to not be helped by TMS. Further, we hypothesized that the difference in baseline symptom ratings induced by the right minus the left lateral visual-field stimulation also might predict the benefit of TMS.
We asked 37 unmedicated outpatients, who met diagnostic criteria for major depression (disease state management = IV) and were enrolled in another ongoing study to test the efficacy of rTMS' management of depression, to also participate in the present experiment. Therefore, the 37 patients studied here represent a subset of those entered in a larger investigation on the antidepressant effects of rTMS. In this larger investigation, patients are randomized to receive different schedules and parameters of rTMS. For the purpose of the current study, we selected only those consecutive patients who had been randomized to receive 10-Hz stimulation to the left dorsolateral prefrontal cortex. All gave written informed consent to the study that was approved by the Institutional Review Board.
Of the 37 patients studied, 26 were women and 11 men. The patients' mean age (炳 SD) was 45 炳 11 years. Of the 26 women, 7 were left-handed, whereas only one of the 11 men was left-handed according to the Oldfield Questionnaire. Table 1 summarizes the demographic characteristics of the patients. Inclusion criteria in the study included a history of unipolar recurrent major depressive disorder, absence of other psychiatric axis I diagnoses, absence of long-term medical or neurologic conditions, and failure of at least three adequate medication trials for the current depressive episode.
During the baseline evaluation before entering the rTMS protocol, all patients underwent a formal interview and rating on the Hamilton Depression Rating Scale (HDRS) by a blinded investigator. In addition, for the purpose of the present experiment, each subject was asked to wear two pairs of safety goggles in random order, each allowing vision only out of 40% of the lateral aspect of one lens (Fig. 1A). In a forced-choice design, one of the experimenters (Alvaro Pascual-Leone) sat directly in front of the patients and asked each to verbally rate how much each goggle changed his or her level of depression after wearing the goggles for 45 seconds using a scale from ?? to +5. A score of 0 indicated no change. If wearing the goggles lessened the depressive symptoms, the patient would rate that improvement from +1 (least) to +5 (most), and if they worsened the depression, the patient would rate the intensity of the change from ?? (least) to ?? (most).
None of the patients were told what their ??oggles' results??might imply. The results were not interpreted for them beyond stating that mood effects of wearing goggles can be quite variable and their significance unclear. The patients were told that we were interested in corroborating Dr. Schiffer's results regarding the differential mood effects of LVF and RVF goggles. Therefore, we might prime the patients to report differential effects of the two different goggles, but the direction of the changes was never implied or in any form suggested.
It is also important to note, that at the time of this ??aseline goggle exposure,??none of the patients were aware of neither the rTMS parameters they had been randomized to receive nor the brain area that would be targeted. We wanted to avoid any bias toward left-or right-sided goggle responses that could have been evoked by the patients' knowledge of the fact that rTMS would be applied to the left dorsolateral prefrontal cortex.
According to a study protocol aimed at studying the effects of different frequencies and localization of rTMS in depression, a physician, blind to the results of the ??oggles' interview??and unaware of this experiment, gave each patient rTMS for 2 weeks. Stimulation was applied using a Magstim Super Rapid Magnetic Stimulator (The Magstim Company, Wales, U.K.) and a focal, eight-shaped, double coil (7-mm diameter per each wing). In all patients studied in the present experiment, TMS was applied to the left dorsolateral prefrontal cortex as defined by previously published guidelines ( 5 ). In all the patients included in the present experiment, rTMS was applied for 10 days (Monday thru Friday during 2 consecutive weeks) at 10-Hz frequency and 110% of motor threshold intensity. Each patient received 1600 stimuli per session delivered in 20 trains of 8 seconds' duration with 22-second intertrain intervals (26.6-minute long sessions). Transcranial magnetic stimulation was applied under an investigational device exemption from the Food and Drug Administration. Stimulation parameters were within published safety guidelines and recommendations (21 ,22 ). Motor threshold, and thus TMS intensity, was determined by following the guidelines and methodology endorsed by the International Federation of Clinical Neurophysiology.
Rating the severity of depression was done by using the HDRS. The evaluator was blinded to the results of the ??oggles' evaluation,??as well as to the rTMS condition. Evaluation was conducted at baseline, just before TMS, shortly after the end of the 2-week TMS course, and at 2 weeks after TMS, that is, at 4 weeks after the baseline HDRS.
We present our raw data, indicating gender and handedness. For our analysis, we decided to center our evaluation on the percent change in HDRS score from baseline to 4 weeks (HDRS.4%) and to relate this change in response to rTMS to the differences between the RVF and the LVF goggle scores at baseline. We decided to collapse lateral visual-field stimulation scores in three groups: RVF?閿VF greater than 0, RVF?閿VF equals 0, and RVF?閿VF less than 0, because we wanted to focus more on the side rather than the intensity of lateral visual-field stimulation, and because we had not validated our ????5 scale. We used an ANOVA with a Tukey-Kramer test to evaluate the differences in HDRS.4% among the three lateral visual-field stimulation groups.
Because a 20% reduction in HDRS can be regarded as a point of discrimination between responders and nonresponders to a given treatment (rTMS in our case), we decided to compare the percentage of patients who responded to rTMS between the two main groups of goggle responses: RVF?閿VF greater than 0 and RVF?閿VF less than 0. We used a Fisher exact test to test this data.
We decided to repeat these identical analyses using higher cutoffs of RVF?閿VF greater than 2, RVF?閿VF less than 2 and greater than ??, and RVF?閿VF less than ?? to divide the patients according to their responses to the lateralized goggles. We used an ANOVA with a Tukey-Kramer test and a 2 test to evaluate this data statistically.
A paired t test was used to compare the HDRS scores at 2 and at 4 weeks.
All patients tolerated the rTMS without unexpected complications. As for the more common risks and side-effects of rTMS (21 ), none of the patients experienced a seizure or neck pain. However, almost 20% of our patients reported of muscle tension and headache, and many took acetaminophen for the pain. In all cases, patients rated their headaches as ??ild.??In no instance did any of the patients consider ending their participation in the study because of this side-effect. In none of the patients was the headache recurrent with each daily rTMS session. Rather, in most patients, the headache was present on the first rTMS day but not after the subsequent rTMS session. Therefore, we wonder whether the anxiety provoked by the unknown nature of the rTMS procedure might be a critical contributing factor to the induction of headache by rTMS. In any case, the headache was always short lasting, and all patients reported either self-limited discomfort lasting only approximately 1 or 2 hours, or a prompt resolution of the discomfort with the intake of acetaminophen.
For all 37 subjects, there was a mean baseline HDRS score of 29.6 炳 SD 5.6. There was no significant difference by paired t test (t = ??.26, df = 36, p = ns) between the percent reduction in HDRS scores at 2 and 4 weeks. Therefore, in our analysis we will focus on the clinically more important HDRS score at 4 weeks. We found a mean percent change in HDRS score at 4 weeks of ??8.6% 炳 SD 29.6, with a range from ??.7% to ??1.3%. Of the 37 patients, 51.4% had a change in HDRS score at 4 weeks of at least ??0%. We ran multiple regression models using gender, handedness, age, and baseline HDRS score, individually and in combinations to predict the percent change in HDRS score at 4 weeks. However, we found no model that approached significance.
In response to the RVF goggle, all 37 patients reported feeling less depressed (57%) or more depressed (43%); none of the patients reported no change. With the LVF goggle, 46% reported feeling an improvement, 32% a worsening, and 22% no change. Thirty-five of the 37 patients (94.6%) had an absolute difference between the two lateral visual fields of at least one point (on our 10-point depression scale), and 64.9% had at least a 3-point difference. The side on which a patient felt more depression varied between individuals. Of the 35 patients who felt at least a one-point difference between sides, 20 felt a more negative effect looking to the LVF, implying a more negative effect in the right hemisphere (11 ). Fifteen other patients reported a greater negative affect looking to the RVF, implying a more negative affect in the left hemisphere ( 11 ). Figure 2 presents our raw data indicating gender and handedness.
FIG. 2. The raw data for the relation between the percent decrease in the Hamilton Depression Rating Scales from baseline to week 4 (HDRS.4%) and the emotional score (?? = ??xtremely worse??to +5 = ??xtremely better?? in response to (A) the right visual-field goggle (RVF, thought to stimulate the left hemisphere), (B) to the left visual-field goggle (LVF, thought to stimulate the right hemisphere), and (C) for RVF?閿VF. Males are indicated by the symbol ??,??and females are indicated by the symbol ??.??Symbols for right-handed people are in bold.
There was a tendency for those patients who felt an improvement with the lateralized goggles when looking to the right to experience a worsening when looking to the left visual field, as well as a tendency for those who felt improvement looking to the left to experience a worsening when looking to the right. For example, there was a significant negative correlation, r = ??.59, p < 0.0001, between the LVF and the RVF goggles' responses among all 37 patients. Among the 29 right-handers, this correlation was r = ??.67, p < 0.0001.
Among the 20 patients who reported a more positive effect when looking to the RVF (stimulating the left hemisphere) than to the LVF, (RVF?閿VF > 0), there was a mean (炳 SD) change in HDRS score at 4 weeks of ??2.3% (炳 28.4). For the 15 patients who reported a more positive effect while looking to the opposite side (RVF?閿VF < 0), the change in HDRS was only ??1.3 (炳 22.2). Finally, for the two patients who reported no change between sides (RVF?閿VF = 0), the change in HDRS score was ??2.4 (炳 31.7) ( ). We compared the HDRS.4% among these three groups of lateral visual-field stimulation responses and found a significant difference by ANOVA, (F [2,34] = 6.104, p = 0.0054). By a Tukey-Kramer test we found a significant difference only between the RVF?閿VF greater than 0 and the RVF?閿VF less than 0 groups (p < 0.01).
FIG. 3. The mean percent decrease in the Hamilton Depression Rating Scale at 4 weeks after baseline for the three categories of responses to the goggles: RVF?閿VF greater than 0, RVF?閿VF equals 0, and RVF?閿VF less than 0. The differences between the three groups were significant by ANOVA, F (2,34) = 6.104, p = 0.0054. A Tukey-Kramer test indicated a significant difference only between the RVF?閿VF greater than 0 and the RVF?閿VF less than 0 groups, p < 0.01.
When we divided the patients according to the higher cutoff of RVF?閿VF greater than 2, RVF?閿VF less than 2 but greater than ??, and RVF?閿VF less than ??, we found the first group (n = 12) had a mean HDRS score at 4 weeks of ??3.8% 炳 (25.8); the second group (n = 13), ??0.3% (30.9); and the third group (n = 12), ??1.7 (24.2). We compared the HDRS.4% among these three groups of lateral visual-field stimulation responses and found a significant difference by ANOVA, (F [2,34] = 4.22, p = 0.023). By a Tukey-Kramer test we found a significant difference only between the RVF?閿VF greater than 2 and the RVF?閿VF less than ?? groups, (p < 0.05).
Because a 20% reduction in HDRS score might be considered to have some clinical relevance, we decided to compare the frequency of such positive responses to rTMS among the three groups of lateral visual field stimulation responders. As shown in看 Table 2 , among the 20 patients who had goggle responses to RVF?閿VF greater than 0, 75% had at least a 20% reduction in HDRS.4%, and among the 15 patients who had the opposite goggle response (RVF?閿VF less than 0), 80% had less than a 20% reduction in HDRS.4% (two-tailed Fisher exact test, p = 0.002).
When we divided the patients according to the higher cutoff of RVF?閿VF greater than 2, RVF?閿VF less than 2 but greater than ??, and RVF?閿VF less than ??, we found that 83% of the first group (10 of 12) had more than a 20% reduction in HDRS.4%; whereas 54% of the second group (6 of 13) and 16.7% of the third group (2 of 12) had this degree of reduction in HDRS.4% by 2 (10.7, df = 36, p < 0.005).
Ten patients had at least a 50% reduction in HDRS.4%. A 50% reduction in HDRS is often considered to indicate a positive response to treatment. Of the 10 patients who achieved this level, nine were in the lateral visual-field stimulation group; RVF?閿VF was greater than 0. The patient who was the exception was a left-handed woman.
There are no differences that approached significance between left-and right-handed people on any of the following measures: baseline HDRS; HDRS.4%; or goggle scores on RVF, LVF, or RVF?閿VF. Because many studies on laterality exclude left-handed people, we decided to examine the results for the 29 right-handers alone. The results for this group did not differ greatly from the results for the full group of 37. Among the 16 patients who reported a more positive effect looking to the RVF than to the LVF, there was a mean (炳 SD) percent change in HDRS score at 4 weeks of ??2.7% (炳 29.9). Seven (44%) of these patients achieved at least a 50% reduction in HDRS by week 4. For the 12 patients who reported a more positive effect while looking to the opposite side (RVF?閿VF less than 0), the change in HDRS was only ??.9% (炳 10.8). In this group of 12, none achieved a 50% reduction in HDRS, and 10 (83%) did not achieve even a 20% decrease in HDRS.
Repetitive TMS is a relatively safe, painless, convenient, experimental treatment for patients who are depressed. It is highly effective in some patients, but a significant percentage of patients are not helped. This large interindividual variability might contribute to the disparity in results among trials of rTMS in depression. Overall, the size of the antidepressant effects of rTMS in the patients reported in this study is quite consistent with the literature.
Among the severely depressed, treatment-resistant patients in this study, we found an overall decrease in the HDRS score of nearly 30%?螿ess than some previously reported data ( 15 ,18 ) but more than other (19??1 ), similarly, controlled trials of TMS in depression (for review see [ 5 ,6 ]). Certainly, increased understanding about the mechanisms of action to rTMS might help minimize the variability of the results of rTMS trials in depression by allowing better-suited rTMS parameters, application methodology, and patient selection. In the current study, we sought a method for predicting which patients were more likely to benefit from rTMS. Accurate predictions might markedly increase the rate of positive responses by selecting those patients more likely to benefit from this treatment.
Although there is a general impression in the field that the right hemisphere is associated with emotion, and especially with negative emotion ( 24 ), most of the studies on when this impression is based reported average data. Just as, on average, men are taller than women, average data should not be regarded without exception. As discussed in greater detail by Schiffer (11 ,13 ), many studies contradict the idea that negative emotion is associated primarily with the right hemisphere in all individuals. We believe this finding may be useful to assess hemispheric differences in affect on an individual basis and suggest that lateral visual-field stimulation may be a useful tool for that assessment.
We wish to be clear that lateral visual stimulation does not limit stimulation, as in split-brain patients, to one hemisphere. It has, however, been shown in a number of experiments that sending more stimulation to the contralateral hemisphere can shift hemispheric dominance to that side. For instance, Wittling et al (25??8 ) showed movies to the lateral visual field of different populations and found differences in affect, heart rate, blood pressure, and cortisol levels depending on which hemisphere the films were shown and to which group they were shown. Lempert and Kinsbourne (19 ) found that college students simply looking to the left side performed better on a language task than when they performed the identical task looking to the right side. Because looking to the right was thought to activate the left hemisphere, the side better at most linguistic tasks, their conclusion was that simply looking to one side could shift hemispheric dominance. Levick et al (17 ) used contact lenses, which were opaque except for an area on one side of the lenses, forcing visual stimulation to go primarily (but not exclusively) to the contralateral hemisphere. Like Lempert and Kinsbourne, they found that looking to the right resulted in a significant improvement in the performance of a language task. They also demonstrated several other tests of shifts in hemispheric dominance to the contralateral side including shifts in theta-electroencephalogram activity over the frontal and temporal leads, the same electroencephalogram changes that we reported with the taped experimental goggles but not with the placebo controls (12 ). Visual stimulation is not the only modality that when applied unilaterally can shift hemispheric dominance. Lateralized auditory and tactile stimuli (29 ), as well as lateral visual (29 ,30 ), have been shown by functional imaging to induce increases in contralateral activity. Furthermore, Schiff et al show that unilateral muscle contractions can induce changes in affect (20 ,31 ,32 ) and changes in persistence on a behavioral task (20 ).
Thus, several groups have reported changes in cognitive and affective states with changes in lateral sensory or motor stimulation. These authors have attributed these cognitive and affective changes to the shift in cerebral dominance caused by lateral stimulation. A comprehensive review of this literature is beyond the scope of this paper, but has been recently published elsewhere (13 ).
In an earlier report (16 ), Schiffer found that the majority (71%) of 21 patients with major depression responded to the lateralized goggles with at least a 20% difference between sides. Of these, 73% experienced more negative affect looking out of the LVF that was hypothesized to relatively activate the right hemisphere. In the current study of 37 patients with depression, 78% had at least a 20% difference in negative affect between sides; 57% of these had a greater amount looking to the LVF. We found that TMS, applied to the left frontal area at a frequency predicted to enhance cortical excitability ( 10 ), tended to benefit those patients who experienced with lateral visual-field stimulation an improvement when looking to the right (thought to activate relatively the left hemisphere), but not those with the opposite lateral visual-field stimulation response.
In an attempt to consider explanations other than our hypothesis for the significant results we observed, we wondered if lateral visual-field stimulation might detect placebo responders rather than predict therapeutic responses to TMS. We cannot absolutely rule out this possibility, but we have no hypothesis on which to expect that the side of the positive lateral visual-field stimulation response would predict a placebo response. Because the overall response to TMS was a modest 28% reduction in HDRS.4%, one could wonder whether the TMS improvements were caused by placebo effects, but because the TMS reductions in the RVF?閿VF greater than 0 group were an impressive 42%, we believe that a placebo effect may be less likely in this group. Studies are in progress to compare TMS with sham TMS. Furthermore, we believe that if lateral visual-field stimulation could by some means predict placebo responses, this would be an important contribution, but, at the present time, we have no convincing explanation or evidence for this ability.
In the future, we plan to evaluate whether patients who have RVF?閿VF less than 0 would have positive responses to right frontal rTMS. We also hope to further study lateral visual-field stimulation to learn whether it can affect corticospinal excitability as a marker of lateralized cortical excitability changes.
Supported in part by grants from the National Institute of Mental Health (RO1-MH5790), National Alliance for Research in Schizophrenia and Depression, and the Stanley Vada Foundation. The authors appreciate the advice of Meredith Regan, ScD, of Beth Israel Deaconess Medical Center, on the statistical analysis. Julian P. Keenan, Stefanie Freund, Fumiko Maeda, Shirlene Sampson, and Robert Birnbaum performed the transcranial magnetic stimulation in the different patients.