Abstract
We studied the effects of rapid-rate transcranial magnetic stimulation (rTMS) of different scalp positions on mood Ten normal volunteers rated themselves before and after rTMS on five analog scales labeled ``Tristeza'' (Sadness), ``Ansiedad'' (Anxiety), ``Alegria'' (Happiness), ``Cansancio'' (Tiredness), and ``Dolor/Malestar'' (Pain/Discomfort). rTMS was applied to the right lateral prefrontal, left prefrontal, or midline frontal cortex in trains of 5 seconds' duration at 10 Hz and 110% of the subject's motor threshold intensity. Each stimulation position received 10 trains separated by a 25-second pause. No clinically apparent mood changes were evoked by rTMS to any of the scalp positions in any subject. However, left prefrontal rTMS resulted in a significant increase in the Sadness ratings (Tristeza) and a significant decrease in the Happiness ratings (``Alegria'') as compared with right prefrontal and midfrontal cortex stimulation. These results show differential effects of rTMS of left and right prefrontal cortex stimulation on mood and illustrate the lateralized control of mood in normal volunteers.
NEUROLOGY 1996,46 499-502.
Studies of hemispheric language dominance using rapid-rate transcranial magnetic stimulation (rTMS) have found affective reactions in a considerable number of subjects following left (dominant) frontal cortex stimulation. [1-3] Subjects have reported frustration and sadness and have even burst into tears. The source of these emotions is unclear and has been ascribed to the distressing sensation associated with the rTMS-induced speech arrest. However, a direct, lateralized effect of rTMS on mood must be considered.
George et al. [4] suggested that prefrontal lobe dysfunction is relevant in the pathophysiology of affective disorders. Several studies support the notion of a lateralized effect of left and right prefrontal cortex on mood. Ischemic damage to the left, rather than the right, frontal cortex is frequently associated with post-stroke depression. [5] Patients with multiple sclerosis and comorbid depression have significantly more plaques in the left-hemispheric white matter than nondepressed patients with similarly severe multiple sclerosis. [6] During intracarotid sodium amobarbital procedures, inactivation of the left, but not the right, hemisphere frequently produces a negative mood state. [7] Pardo et al [8] showed that left prefrontal cortex activity increases when subjects are asked to think sad thoughts. Finally, several structural (CT and MRI) and functional neuroimaging studies (SPECT and PET) have described abnormalities in left prefrontal cortex in primary and secondary depression. [4]
The aim of the present study was to investigate whether rTMS induced measurable changes in mood depending on whether left or right prefrontal cortex was stimulated.
Methods.
Subjects.
We studied 10 normal volunteers (six men and four women) aged 22 to 27 years. All subjects were recruited among non-medical students at the University of Valencia. All had normal physical and neurologic examinations. None had a personal or family history of neurologic diseases or mood disorders. All met the safety criteria outlined for rTMS in normal volunteers by Pascual-Leone et al. [9] All subjects were naive to rTMS and unaware of the aim of the study. All gave their informed consent prior to entering the study, which had been approved by the institutional review board.
Experimental design.
The subjects were initially asked to rate themselves on five analog scales labeled ``Tristeza'' (Sadness), ``Ansiedad'' (Anxiety), ``Alegria'' (Happiness), ``Cansancio'' (Tiredness), and ``Dolor/Malestar'' (Pain/Discomfort). The scales were presented as five 10-cm lines arranged one above the other with an arrow on the top right corner labeled ``mas de lo normal'' (greater than normal) and an arrow on the top left corner labeled ``menos de lo normal'' (less than normal). These scales were presented on a single page, and their order was random and counterbalanced across subjects. The subjects were asked to transect each line indicating the subjective rating in each one of the categories. They were specifically told that there were no correct or incorrect answers and that they should try to complete the task quickly without giving it too much thought, but rather following their first inclination No further instructions were given.
Thereafter, all subjects received rTMS to the right prefrontal cortex, the left prefrontal cortex, and the midfrontal cortex. Each area was stimulated twice. The order of the stimulated areas was random and counterbalanced across subjects. Immediately after stimulation to each area, the subjects were requested to rate themselves in the five categories in the same manner as described above. Therefore, each subject rated himself or herself in all five categories a total of seven times, once prior to any rTMS and once after each of two trains of stimulation applied to each of three scalp locations. The order of the scales was randomly varied across the successive ratings within and across subjects.
Repetitive transcranial magnetic stimulation.
We used a Cadwell High Speed Magnetic Stimulator equipped with a specially designed 8-shaped coil that allows continuous water cooling in order to prevent overheating during long stimulation trains. Each wing in the coil measures approximately 7 cm in diameter. Technical characteristics of this stimulator and coil have been previously described. [1,9,10]
Stimulation was applied either to the left prefrontal, right prefrontal, or midfrontal cortex. The coil was held flat on the scalp with the intersection of the two wings centered over the stimulation position. Midfrontal cortex stimulation refers to rTMS with the coil centered 5 cm anterior to the optimal scalp position for induction of motor evoked potentials in the anterior tibialis muscles. Stimulation of the right or left prefrontal cortex refers to rTMS with the coil centered along the lateral convexity 5 cm rostral to the optimal position for induction of motor evoked potentials in the abductor pollicis brevis muscle in the contralateral hand. Wassermann et al [11] have shown that the optimal scalp position for induction of motor evoked potentials in hand muscles using TMS corresponds to activation of the hand area representation of the anterior bank of the central sulcus, i.e., primary motor cortex. The definition of the stimulation positions in the present study as measured from the presumed site of the central sulcus is based on the Tailarach Atlas coordinates in order to influence predominantly the right and left dorsolateral prefrontal cortex and the anterior cingulate and rostral supplementary motor cortex (midline stimulation position).
Stimulation was applied at 110% of the subject's motor threshold Motor threshold was determined by the method of limits and was defined as the lowest stimulation intensity capable of inducing five motor evoked potentials in the right abductor pollicis brevis muscle of at least 50 mu V in a series of 10 single magnetic stimuli with the coil centered over the optimal scalp position. Stimulation was delivered in trains of 5 seconds' duration and 10-Hz stimulation frequency. In each stimulation session, each subject received 10 trains of stimulation separated by 25-second pauses. Each stimulation session, therefore, lasted nearly 5 minutes, and each subject received a total of 500 stimuli per session. Immediately after each stimulation session, the subjects were asked to complete the self-rating in the five analog scales. Thereafter, we waited at least 30 minutes before applying the next rTMS session. Since each subject received rTMS twice to three scalp positions, a total of six stimulation sessions was applied, totaling approximately 3,000 stimuli. The experiment lasted approximately 3.5 hours because of the long rest periods between rTMS sessions.
Safety of these stimulation values is supported by the available safety studies on rTMS. [9,10,12] Safety concerns of rTMS are discussed elsewhere. [9,10] As part of the informed consent prior to entering the study, potential risks of the stimulation were discussed in detail with all subjects. Stimulation sessions were performed by trained neurologists in a room equipped with the necessary instruments and medications for the prompt treatment of a possible seizure. All patients wore earplugs during the stimulation session.
Results.
All the subjects tolerated the stimulation without complications. None of them reported feeling any different after the rTMS to any scalp position, and no clinically detectable mood changes were noted in any of the subjects regardless of rTMS site. Six of the 10 subjects spontaneously reported that rTMS over the left prefrontal cortex was more unpleasant than over the other two scalp positions. None of the subjects complained of a lasting headache or required any treatment for complications.
The baseline ratings in the five different scales showed little variability across subjects. All subjects tended to transect the lines approximately at the middle. No salient baseline mood differences were noted clinically across subjects, and the baseline ratings were not considered in their absolute value for the further analysis of the results. Rather, ratings after the different rTMS sessions were expressed as difference from the baseline ratings, positive if they were closer to the right end of the analog scale or negative if they were closer to the left end Figure 1.
Figure 1*. Bar histograms of the effects of rTMS on the ratings in the five scales depending on stimulation position. The results indicate the mean (plus minus standard deviation) distance (cm) from the baseline rating to the rating after rTMS for all 10 subjects
Overall effects of rTMS on the different ratings according to stimulation position were analyzed separately for each rating using one-way analysis of variance (ANOVA) for repeated measurements after collapsing across subjects. ANOVA for Cansancio (Tiredness) showed no significant overall effect of rTMS according to stimulation position (F value equals 0 76, df equals 2, p equals 0.47). ANOVA for Dolor/Malestar (Pain/Discomfort) showed a significant overall effect of stimulation by rTMS position (F equals 4.28, df equals 2, p equals 0.02). However, post hoc Scheffe's test showed significant paired comparison only for midfrontal versus left prefrontal stimulation (p equals 0.04), with left rTMS being more painful. ANOVA for Ansiedad (Anxiety) showed a significant overall interaction between rating and rTMS stimulation position (F equals 4.48, df equals 2, p equals 0.02). Post hoc Scheffe's test showed a significant difference only between midfrontal and left prefrontal stimulation (p equals 0.02), with left stimulation inducing greater anxiety. ANOVA for Alegria (Happiness) also showed a significant overall effect (F equals 4 73, df equals 2, p equals 0.01). Post hoc Scheffe's test showed a significant difference only for the comparison between right and left prefrontal stimulation (p equals 0.01), with ratings increasing following right prefrontal rTMS, but decreasing following left prefrontal rTMS. However, the most striking results were noted in the ratings for Tristeza (Sadness). ANOVA for this category showed a highly significant overall effect of rTMS on rating according to stimulation position (F equals 34.96, df equals 2, p less than 0.0001), and post hoc Scheffe's test showed significant paired comparisons for left prefrontal versus midfrontal (p less than 0.0001) and versus right prefrontal cortex stimulation (p less than 0.0001). Ratings for Tristeza (Sadness) were higher following rTMS to all sites, but the increase was much greater after left prefrontal stimulation.
Therefore, even though no clinically apparent mood changes were evoked by rTMS to scalp positions in any of the subjects, the subjective ratings showed a highly significant effect of left prefrontal rTMS on mood. Left prefrontal rTMS resulted in a significant increase in the Sadness ratings (Tristeza) and a significant decrease in the Happiness ratings (Alegria) as compared with right prefrontal and midfrontal cortex stimulation. Nevertheless, none of the subjects predicted the results, and all commented with some surprise on the differences of their own ratings depending on stimulation site.
Discussion.
We found that rTMS of the left prefrontal cortex was associated with a significant increase in subjective ratings in the Tristeza (Sadness) scale and a significant decrease in the ratings in the Alegria (Happiness) scale. Destructive lesions of the left prefrontal cortex frequently result in depressive mood disorders, [5,13,14] and several functional neuroimaging studies have shown that patients with primary or secondary depression [15-20] have decreased metabolism or cerebral blood flow in the left anterolateral prefrontal cortex. Our results are in agreement with these findings provided that rTMS caused a transient hypofunction of the underlying cortex, but the precise biological effect of rTMS on the cortex is uncertain and seems dependent on stimulation intensity and frequency. [10]
We cannot eliminate the possibility that rTMS might have transiently increased the excitability of the underlying cortex. An example of the divergent effects of TMS on cortical excitability, and thus on behavior depending on stimulation conditions and values, is illustrated by the studies of TMS on motor reaction time. Subthreshold TMS can speed up reaction time, [21] whereas suprathreshold TMS causes a delay in reaction time. [22] Cortical stimulation studies have demonstrated that the afterdischarge threshold of the motor cortex is lower than that of the prefrontal cortex. [23] Therefore, even though we applied rTMS at intensities slightly above those required to evoke motor potentials when stimulating the motor cortex, it is uncertain whether this intensity might have been subthreshold or suprathreshold for the prefrontal cortex.
Thinking sad thoughts is associated with left prefrontal hyperactivity in normal volunteers [8] and patients with underlying familial pure depressive disorders. [18] George et al. [24] have recently replicated these findings and shown that the increased left prefrontal activity is specific for sadness as compared with transient happiness. rTMS possibly led to a transient hyperactivity of the left prefrontal cortex and resulted in the higher Sadness and lower Happiness ratings. Therefore, the physiologic basis of the effects of rTMS of the left prefrontal cortex on mood is unclear.
Higher discomfort induced by left prefrontal cortex rTMS could have influenced mood ratings and led to higher ratings in Sadness and lower ratings in Happiness. In fact, most subjects reported spontaneously feeling more distressed by left than right or midline frontal stimulation. However, the individual subjective ratings in the analog scale for Dolor (Pain) did not show any significant differences between rTMS position in any of the subjects and overall effects were only minimally significant. Therefore, we feel that our results cannot be accounted for simply by the discomfort induced by rTMS.
The effects of rTMS on mood may have been much longer lasting than the 30 minutes that we allowed between stimulation trains. Therefore, preceding stimulation effects might have introduced a bias on the results of subsequent rTMS trains. We tried to control for this by randomizing the stimulation positions, but studies with longer follow-up of subjects after stimulation to each scalp position and baseline ratings before each stimulation of each position would be valuable.
In summary, our results show differential effects of rTMS of left and right prefrontal cortex stimulation on mood. These effects must be considered when interpreting results of studies of cognitive functions with rTMS. Further studies applying rTMS at different stimulation intensities and frequencies are needed to determine the physiologic basis of the observed effects on mood. We believe, however, that rTMS is suited for the noninvasive study of the control of mood in normal volunteers and might be helpful in investigating the pathophysiology of depression.
Acknowledgments
We thank Cadwell Inc for making the High Speed Magnetic Stimulator available to us and for their technical support, and Drs. M. George and E.M. Wassermann for the critical review of the manuscript.
- Copyright 1996 by the Advanstar Communication Inc.
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