Dynamic changes in spatial representation within the posterior parietal cortex in response to visuomotor adaptation.

Recent studies used functional magnetic resonance imaging (fMRI) population receptive field (pRF) mapping to demonstrate that retinotopic organization extends from the primary visual cortex to ventral and dorsal visual pathways, by quantifying visual field maps, receptive field size, and laterality throughout multiple areas. Visuospatial representation in the posterior parietal cortex (PPC) is modulated by attentional deployment, raising the question of whether spatial representation in the PPC is dynamic and flexible, and whether this flexibility contributes to visuospatial learning. To answer this question, changes in spatial representation within the PPC and early visual cortex were recorded with pRF mapping before and after prism adaptation (PA)-a well-established visuomotor technique that modulates visuospatial attention according to the direction of the visual displacement. As predicted, results showed that adaptation to left-shifting prisms increases pRF size in left PPC, while leaving space representation in the early visual cortex unchanged. This is the first evidence that PA drives a dynamic reorganization of response profiles in the PPC. These findings show that spatial representations in the PPC not only reflect changes driven by attentional deployment but dynamically change in response to modulation of external factors such as manipulation of the visuospatial input during visuomotor adaptation.

Motor cortex excitability correlates with an anxiety-related personality trait.

BACKGROUND: In an earlier study comparing obsessive-compulsive disorder (OCD) patients to psychiatrically screened normals, we found lowered motor evoked potential (MEP) threshold to transcranial magnetic stimulation (TMS) and decreased intracortical inhibition in OCD. We sought to determine whether this pattern was specific to OCD. METHODS: We measured the threshold and amplitude of MEPs to single and paired (subthreshold-suprathreshold; 3, 4, 10, 15 msec intervals) TMS in 46 healthy volunteers (23 women, 23 men) who were given the NEO-PI-R personality inventory. Nineteen of the men also received cognitive and motor tests. RESULTS: The paired-pulse conditioned/unconditioned MEP amplitude ratios correlated with Neuroticism (N), a stable measure of trait-level anxiety and other negative emotions, in the whole sample (r = 0.48; p = 0.0006), and in the men (r = 0.63; p = 0.0009). There were no other significant correlations. CONCLUSIONS: This relationship reflects a factor that contributes to both personality and cortical regulation. It was not statistically significant in women, probably because of confounding hormonal influences on excitability. Decreased intracortical inhibition may be related more to trait anxiety and depression, which are high in OCD, than to OCD itself. However, the MEP threshold (significantly lowered in OCD) was unrelated to N.

Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients.

BACKGROUND: High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L >> R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.

Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

BACKGROUND: Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. METHODS: We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS. RESULTS: We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. CONCLUSIONS: These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study.

OBJECTIVE: Prefrontal mechanisms are implicated in obsessive-compulsive disorder. The authors investigated whether prefrontal repetitive transcranial magnetic stimulation influenced obsessive-compulsive disorder symptoms. METHOD: Twelve patients with obsessive-compulsive disorder were given repetitive transcranial magnetic stimulation (80% motor threshold, 20 Hz/2 seconds per minute for 20 minutes) to a right lateral prefrontal, a left lateral prefrontal, and a midoccipital (control) site on separate days, randomized. The patients' symptoms and mood were rated for 8 hours afterward. RESULTS: Compulsive urges decreased significantly for 8 hours after right lateral prefrontal repetitive transcranial magnetic stimulation, but there were nonsignificant increases in compulsive urges after repetitive transcranial magnetic stimulation of the midoccipital site. A shorter-lasting (30 minutes), modest, and nonsignificant reduction in compulsive urges occurred after left lateral prefrontal repetitive transcranial magnetic stimulation. Mood improved during and 30 minutes after right lateral prefrontal stimulation. CONCLUSIONS: These preliminary results suggest that right prefrontal repetitive transcranial magnetic stimulation might affect prefrontal mechanisms involved in obsessive-compulsive disorder.

Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial.

OBJECTIVE: Preliminary studies have indicated that daily left prefrontal repetitive transcranial magnetic stimulation might have antidepressant activity. The authors sought to confirm this finding by using a double-blind crossover design. METHOD: Twelve depressed adults received in random order 2 weeks of active treatment (repetitive transcranial magnetic stimulation, 20 Hz at 80% motor threshold) and 2 weeks of sham treatment. RESULTS: Changes from the relevant phase baseline in scores on the 21-item Hamilton depression scale showed that repetitive transcranial magnetic stimulation significantly improved mood over sham treatment. During the active-treatment phase, Hamilton depression scale scores decreased 5 points, while during sham treatment the scores increased or worsened by 3 points. No adverse effects were noted. CONCLUSIONS: These placebo-controlled results suggest that daily left prefrontal repetitive transcranial magnetic stimulation has antidepressant activity when administered at these parameters. Further controlled studies are indicated to explore optimal stimulation characteristics and location, potential clinical applications, and possible mechanisms of action.

Decreased postexercise facilitation of motor evoked potentials in patients with cerebellar degeneration.

We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects and 11 medication-free patients with cerebellar degeneration. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until the muscle fatigued (subject became unable to maintain half maximal force). MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean preexercise MEP amplitude in normal subjects and 132% in cerebellar patients, indicating postexercise MEP facilitation in both groups. However, postexercise MEP facilitation, compared with the mean preexercise MEP amplitude, was not significant in the patients but was significant in the normal subjects. The amplitudes of MEPs recorded within the first few minutes after fatigue were 44% of the mean preexercise MEP amplitudes in both groups. We conclude that in patients with cerebellar degeneration, postexercise MEP facilitation is significantly reduced, whereas postexercise MEP depression after fatigue is similar to that of normal subjects.

Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD.

OBJECTIVE: To reevaluate the effect of subthreshold repetitive transcranial magnetic stimulation (rTMS) on concurrent fine movement in PD. BACKGROUND: A previous study showed a beneficial effect of rTMS on the performance of six patients with PD on the Grooved Pegboard test. METHODS: The authors repeated this experiment in 11 patients with idiopathic PD who performed the test while the stimulating coil discharged continuously at 5 Hz, either over the contralateral motor cortex at just below the threshold for movement, or in the air near the head as a control. Patients were tested twice under both conditions. RESULTS: Although some patients performed faster with rTMS, others showed the opposite effect. There was no significant effect of rTMS in the group, nor did baseline performance or the order of conditions interact with the effect of rTMS. CONCLUSIONS: Based on this larger and more comprehensive study, simultaneous, 5-Hz subthreshold rTMS over the motor cortex does not have consistent or potentially therapeutic effects on movement in PD.

Impaired inhibition in writer's cramp during voluntary muscle activation.

We used paired transcranial magnetic stimulation (TMS) to evaluate inhibitory mechanisms in eight patients with writer's cramp during rest and isometric wrist extension. Both stimuli were 110% of the motor threshold; the interstimulus intervals (ISIs) were 20 to 200 ms in increments of 10 ms. Surface EMG was recorded from wrist extensors. In the symptomatic hemisphere, there was no significant difference in the amplitude of the test (second) motor evoked-potential (MEP) between patients and age-matched controls at rest. However, with voluntary muscle activation, inhibition of the test MEP by the conditioning MEP was significantly less in writer's cramp patients than in controls (p = 0.02). The difference was most prominent at ISIs of 60 to 80 ms in which inhibition is maximum. In the asymptomatic hemisphere, there was no significant difference between patients and controls in both rest and active conditions. The silent period was shorter in patients than controls on the symptomatic side (p = 0.003) but not on the asymptomatic side. We conclude that the inhibitory effects induced by magnetic stimulation are reduced in patients with writer's cramp, but only on the symptomatic side during muscle activation. This may relate to the overflow of muscle activity that characterizes this condition.

Effects of transcranial magnetic stimulation on ipsilateral muscles.

We studied the effects of transcranial magnetic stimulation of the motor cortex on ipsilateral upper extremity muscles in six normal men. Stimulation had inhibitory and excitatory effects on the muscles during voluntary activation. Transient inhibition, an ipsilateral silent period (ISP), occurred in all muscles tested, often without any preceding excitatory response. Motor evoked potentials (MEPs) occurred ipsilaterally in the proximal muscles of some subjects. Ipsilateral MEPs and ISPs were delayed relative to the MEPs evoked by the same stimulus in the corresponding contralateral muscles. The excitability of the alpha motoneuron pool, assessed during the period of the ISP by eliciting H-reflexes, showed no change, suggesting that ipsilateral inhibition acts at a level above the alpha motoneuron. Connections from motor cortex to ipsilateral muscles could be via the corpus callosum and contralateral hemisphere or via purely ipsilateral pathways.

Effects of phenytoin on cortical excitability in humans.

We studied the effects of a loading dose of phenytoin on motor cortex excitability in five healthy volunteers. Phenytoin elevated motor thresholds to transcranial magnetic stimulation (TMS) in all subjects, but had no effects on motor-evoked potential amplitudes, silent period durations, and intracortical excitability tested by paired TMS during rest and voluntary muscle activation. These results are consistent with the hypothesis that blockade of voltage-gated sodium channels decreases membrane excitability and elevates the threshold to TMS, but will not reduce intracortical excitability.

Abnormal cortical motor excitability in dystonia.

To assess the excitability of the motor system, we studied 11 patients with task-specific dystonia and 11 age-matched normal subjects. The dominant side was affected in nine of the patients. We delivered transcranial magnetic stimuli at different stimulus intensities and with different levels of muscle facilitation to the side contralateral to the side of electromyographic recording, and recorded motor evoked potentials (MEPs) from the flexor carpi radialis muscles bilaterally. The threshold intensity for eliciting MEPs at rest did not differ between patients and normal subjects. We compared the affected side in patients with the dominant side in normal subjects. With facilitation, the percentage of the area of the MEP to the M wave (MEP area%) was similar in both groups at low stimulus intensities, but with increasing stimulus intensity the increase in the MEP area% was greater in patients than in normal subjects (ANOVA, p < 0.001). The increase in MEP area% was similar in both groups with increasing facilitation levels. The duration of the silent period was similar in patients and normal subjects. We conclude that cortical motor excitability is increased in dystonia.

Characterization of postexercise facilitation and depression of motor evoked potentials to transcranial magnetic stimulation.

We studied the effects of exercise on motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). Subjects performed 30-second periods of isometric exercise of the extensor carpi radialis until fatigue, which was defined as the inability to maintain half maximum force. The amplitude of MEPs to TMS recorded from the resting muscle after each exercise period was on average more than twice the pre-exercise value (postexercise MEP facilitation). After fatigue occurred, the MEP amplitudes were approximately 60% of the pre-exercise value (postexercise MEP depression). There was a gradual recovery of the depressed MEPs to pre-exercise values over several minutes of rest. Postexercise MEP facilitation was constant when exercise intensity ranged from 10 to 50% of maximum voluntary contraction and it decayed to baseline over several minutes after the end of exercise. There was no postexercise MEP facilitation to TES. We hypothesize that both postexercise MEP facilitation and MEP depression are due to intracortical mechanisms.

Phenytoin does not influence postexercise facilitation of motor evoked potentials.

Postexercise facilitation of motor evoked potentials (MEPs) elicited to transcranial magnetic stimulation occurs after brief, nonfatiguing muscle activation. This phenomenon may be related to post-tetanic potentiation or long-term potentiation (LTP) observed in animal studies. Phenytoin reduces post-tetanic potentiation but does not block LTP. We studied the effects of phenytoin on postexercise MEP facilitation and its decay over time. Phenytoin did not result in either significant change in postexercise MEP facilitation nor significant change in the decay of facilitation. We conclude that postexercise MEP facilitation is unlikely to be secondary to post-tetanic potentiation.

Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation.

We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.

No evidence of hearing loss in humans due to transcranial magnetic stimulation.

Prompted by the description of hearing loss in rabbits exposed to the acoustic artifact of magnetic stimulation, we compared the results of audiologic studies before and after exposure to transcranial magnetic stimulation in humans. We found no evidence of temporary or permanent threshold shifts in any of the subjects, even in those exposed to transcranial magnetic stimulation repeatedly for several years. Risk of hearing loss from the acoustic artifact of magnetic stimulation, as evaluated by audiograms, tympanograms, acoustic reflexes, and auditory evoked potentials, seems to be small in humans.

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression.

We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until they were unable to maintain half maximal force. MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal. The mean amplitudes of MEPs recorded within the first few minutes after the last exercise sets in all three groups were approximately half their mean pre-exercise MEP amplitudes. This postexercise MEP depression was similar in all groups. We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.

Altered cortical excitability in obsessive-compulsive disorder.

OBJECTIVE: To assess cortical inhibitory and excitatory mechanisms in obsessive-compulsive disorder (OCD). BACKGROUND: Transcranial magnetic stimulation (TMS) studies have found decreased neuronal inhibition and a reduced cortical silent period in the primary motor area in Tourette's syndrome, focal dystonia, and other disorders believed to involve dysfunction of subcortical structures, including the basal ganglia. Dysfunction of the basal ganglia and linked regions also has been implicated in OCD, which has significant clinical and familial overlap with tic disorders. METHODS: We applied the TMS techniques previously used in Tourette's syndrome to a group of 16 OCD patients (seven unmedicated) and 11 age-matched healthy volunteers extensively screened for psychopathology. Measures of motor cortex excitability included resting and active motor threshold, cortical silent period duration, and intracortical inhibition and facilitation using a paired-pulse TMS technique with a subthreshold conditioning stimulus. RESULTS: Similar to recent findings in Tourette's syndrome and focal dystonia, this study reports significantly decreased intracortical inhibition (ICI) relative to the volunteers at interstimulus intervals from 2 to 5 msec. We also found decreased active and resting motor evoked potential threshold in the OCD patients, another indication of increased cortical excitability. Neither abnormality appeared medication related. The decreases in ICI and motor threshold were greatest in OCD patients with comorbid tics, but remained significant in patients without tics. CONCLUSIONS: The data suggest abnormal cortical excitability in obsessive-compulsive disorder. These findings are congruent with the hypothesis that Tourette's syndrome and obsessive-compulsive disorder (OCD) are analogous disorders with overlapping dysfunction in corticobasal circuits. Patients with tic-related OCD may have more abnormal motor cortex excitability than OCD patients without tics.

Linguistic processing during repetitive transcranial magnetic stimulation.

To determine if linguistic processing could be selectively disrupted with repetitive transcranial magnetic stimulation (rTMS), rTMS was performed during a picture-word verification task. Seven right-handed subjects were trained in two conditions: picture-word verification, which required the subject to verify whether the picture of an object matched the subtitle name on the same page, and frame verification, which required subjects to verify whether there was a rectangular frame around the combined object picture and subtitle. Half of the trials were performed during rTMS. The effects of rTMS on performance were evaluated at the following four scalp positions: left anterior (the area where rTMS produced speech arrest), a mirror site on the right, and two positions in the left and right parietal region. Stimulation over the left deltoid muscle served as a control. Subjects had less difficulty in making picture-word matching decisions during unstimulated compared with stimulated trials at the left anterior and posterior positions. No significant difference in accuracy was detected in the frame verification condition, but response times in the frame verification condition were longer with stimulation at the left anterior position. Because rTMS of the dominant hemisphere affected linguistic processing independent of speech motor output, we confirm that rTMS may be used to investigate language and other cognitive functions.

Menstrual cycle effects on cortical excitability.

OBJECTIVE: To determine whether there are menstrual cycle-related effects on cortical excitability in normal women. BACKGROUND: Ovarian steroid hormones affect neurotransmission in the brain. Data from animal experiments have shown that progesterone metabolites enhance the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cortex, producing benzodiazepine-like (e.g., diazepam and lorazepam) physiologic and behavioral effects. Estradiol has excitatory effects on measures of neuronal excitability, possibly acting through the glutamate system. These effects have been difficult to detect in women using conventional techniques. However, recently, paired transcranial magnetic stimulation (TMS) has been used to detect the effects of GABAergic and glutamatergic drugs in humans. We used this method to measure the effects of the menstrual cycle in normal women. METHODS: We tested 13 healthy women during the follicular (low-progesterone) and luteal (high-progesterone) phases of the menstrual cycle using paired TMS. The effect of a subthreshold conditioning pulse on the cortex was tested by measuring the response to a second suprathreshold test pulse and comparing it with the response elicited by the test pulse administered alone. RESULTS: Conditioning TMS produced more inhibition in the luteal phase than in the follicular phase (p = 0.01), of similar magnitude to the reported effect of benzodiazepine drugs. CONCLUSIONS: This study provides the first direct evidence of changes in the excitability of a cortical network with the menstrual cycle. The results also show a potential confound for studies using transcranial magnetic stimulation in populations that include menstruating women.