Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation

Functional magnetic resonance imaging and repetitive transcranial magnetic stimulation (rTMS) were used to explore the pathophysiology of auditory/verbal hallucinations (AVHs). Sixteen patients with schizophrenia-spectrum disorder were studied with continuous or near continuous AVHs. For patients with intermittent hallucinations (N = 8), blood oxygenation level-dependent (BOLD) activation maps comparing hallucination and nonhallucination periods were generated. For patients with continuous hallucinations (N = 8) correlations between BOLD signal time course in Wernicke's area, and other regions were used to map functional coupling to the former. These maps were used to identify 3-6 cortical sites per patient that were probed with 1-Hz rTMS and sham stimulation. Delivering rTMS to left temporoparietal sites in Wernicke's area and the adjacent supramarginal gyrus was accompanied by a greater rate of AVH improvement compared with sham stimulation and rTMS delivered to anterior temporal sites. For intermittent hallucinators, lower levels of hallucination-related activation in Broca's area strongly predicted greater rate of response to left temporoparietal rTMS. For continuous hallucinators, reduced coupling between Wernicke's and a right homologue of Broca's area strongly predicted greater left temporoparietal rTMS rate of response. These findings suggest that dominant hemisphere temporoparietal areas are involved in expressing AVHs, with higher levels of coactivation and/or coupling involving inferior frontal regions reinforcing underlying pathophysiology.     

Functional cerebral reorganization for auditory spatial processing and auditory substitution of vision in early blind subjects

Early blind (EB) individuals can recognize bidimensional shapes using a prosthesis substituting vision with audition (PSVA) and activate right dorsal extrastriate visual cortex during the execution of this task. The present study used repetitive transcranial magnetic stimulation (rTMS) to further examine the functional role of this structure in the successful use of the PSVA. Moreover, we investigated which auditory parameter used in the prosthesis (pitch, intensity, or spatial location) might contribute to this occipital activation. Results revealed that rTMS applied to right dorsal extrastriate cortex in EB subjects interferes with both the PSVA use and the auditory spatial location task but not with pitch and intensity discriminations. By contrast, rTMS targeting the same cortical areas in sighted subjects did not affect performance on any auditory tasks. Early visual deprivation thus leads to functional cerebral cross-modal reorganization in the processing of auditory information and auditory-to-visual sensory substitution. The findings also point to the specific involvement of the dorsal visual stream for auditory spatial processing in blind subjects. Moreover, this suggests that sensory substitution prostheses can be developed using these additional neural resources to perform tasks that partially compensate for the loss of vision.     

Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus.

OBJECTIVES: The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low-frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability. STUDY DESIGN: Fusing of the individual PET-scan with the structural MRI-scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8-shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross-over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham-coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller). SETTING: Tertiary referral medical center. RESULTS: Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score. CONCLUSION: These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.     

Suppressing versus releasing a habit: frequency-dependent effects of prefrontal transcranial magnetic stimulation

When subjects are required to generate a random sequence of numbers they typically produce too many forward and backward 'counts' (e.g. 5-6, 4-3). This counting bias is interpreted as the consequence of an interference by overlearned tendencies to arrange numbers according to their natural order. Inhibition of such well-learned routines is known to rely on frontal lobe functioning. We examined differential effects of slow (1 Hz) and fast (10 Hz) repetitive transcranial magnetic stimulation (rTMS) over the left or right dorsolateral prefrontal cortex (DLPFC) on random number generation (RNG) performance. Eighteen healthy men performed an RNG task. Those subjects stimulated over the left DLPFC showed a frequency-dependent rTMS effect: counting bias was significantly reduced after the 1 Hz stimulation compared with baseline, but significantly exaggerated after the 10 Hz stimulation compared with 1 Hz stimulation. In contrast, the sequences of the subjects stimulated over the right DLPFC showed the well-known excess of counting in all conditions (i.e. baseline, 1 Hz and 10 Hz). These findings confirm the functional importance of specifically the left DLPFC in sequential response production and show, for the first time, that rTMS affects cognitive processing in a frequency-dependent manner.     

Human ventral parietal cortex plays a functional role on visuospatial attention and primary consciousness. A repetitive transcranial magnetic stimulation study

In this paper, we used repetitive transcranial magnetic stimulation (rTMS) in 18 normal subjects to investigate whether the ventral posterior parietal cortex (PPC) plays a causal role on visuospatial attention and primary consciousness and whether these 2 functions are linearly correlated with each other. Two distinct experimental conditions involved a similar visual stimuli recognition paradigm. In "Consciousness" experiment, number of consciously perceived visual stimuli was lower by about 10% after rTMS (300 ms, 20 Hz, motor threshold intensity) on left or right PPC than after sham (pseudo) rTMS. In "Attentional" Posner's experiment, these stimuli were always consciously perceived. Compared with sham condition, parietal rTMS slowed of about 25 ms reaction time to go stimuli, thus disclosing effects on endogenous covert spatial attention. No linear correlation was observed between the rTMS-induced impairment on attention and conscious perception. Results suggest that PPC plays a slight but significant causal role in both visuospatial attention and primary consciousness. Furthermore, these high-level cognitive functions, as modulated by parietal rTMS, do not seem to share either linear or simple relationships.     

Effect of physiological activity on an NMDA-dependent form of cortical plasticity in human

Retention of motor learning can be enhanced or degraded by subsequent performance of a different task. Neurophysiologically this may reflect interference in synaptic plasticity by ongoing neural activity in the brain. Here we demonstrate that N-methyl-D-aspartate (NMDA) dependent aftereffects of repetitive transcranial magnetic stimulation (rTMS) also are subject to interference effects, suggesting that it may be possible to investigate these basic mechanisms in the intact human brain. We measured the motor-evoked potential (MEP) amplitude and short-interval intracortical inhibition (SICI) in the first dorsal interosseous (FDI) muscle after continuous or intermittent theta burst (cTBS/iTBS) forms of rTMS. In resting subjects, cTBS depressed MEPs and reduced SICI for about 20 min, whereas iTBS had the opposite effect. However, if subjects contracted the FDI during TBS, then effects on the MEP were abolished, although effects of cTBS on SICI remained. Contraction immediately after TBS enhanced the facilitatory effect of iTBS and reversed the usual inhibitory effect of cTBS into facilitation. Contraction 10 min after cTBS (iTBS not tested) had only a transient (3-4 min) effect on MEPs. These interactions with behavior may relate to mechanisms of interference between learning paradigms in human and be similar to effects on synaptic long-term potentiation/depression described in animal experiments.     

Motor and Gait Improvement in Patients With Incomplete Spinal Cord Injury Induced by High-Frequency Repetitive Transcranial Magnetic Stimulation

Objective:

To assess the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on lower extremities motor score (LEMS) and gait in patients with motor incomplete spinal cord injury (SCI).

Method:

The prospective longitudinal randomized, double-blind study assessed 17 SCI patients ASIA D. We assessed LEMS, modified Ashworth Scale (MAS), 10-m walking test (10MWT), Walking Index for SCI (WISCI II) scale, step length, cadence, and Timed Up and Go (TUG) test at baseline, after the last of 15 daily sessions of rTMS and 2 weeks later. Patients were randomized to active rTMS or sham stimulation. Three patients from the initial group of 10 randomized to sham stimulation entered the active rTMS group after a 3-week washout period. Therefore a total of 10 patients completed each study condition. Both groups were homogeneous for age, gender, time since injury, etiology, and ASIA scale. Active rTMS consisted of 15 days of daily sessions of 20 trains of 40 pulses at 20 Hz and an intensity of 90% of resting motor threshold. rTMS was applied with a double cone coil to the leg motor area.

Results:

There was a significant improvement in LEMS in the active group (28.4 at baseline and 33.2 after stimulation; P = .004) but not in the sham group (29.6 at baseline, and 30.9 after stimulation; P = .6). The active group also showed significant improvements in the MAS, 10MWT, cadence, step length, and TUG, and these improvements were maintained 2 weeks later. Following sham stimulation, significant improvement was found only for step length and TUG. No significant changes were observed in the WISCI II scale in either group.

Conclusion:

High-frequency rTMS over the leg motor area can improve LEMS, spasticity, and gait in patients with motor incomplete SCI.     

Which tinnitus patients benefit from transcranial magnetic stimulation?

OBJECTIVES: Chronic tinnitus is associated with hyperactivity of the central auditory system. Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a treatment for chronic tinnitus. This study determined the factors that predict a beneficial outcome with rTMS treatment. STUDY DESIGN: Forty-five patients with chronic tinnitus underwent 10 sessions of low-frequency rTMS to their left auditory cortex. The treatment outcome was assessed with a tinnitus questionnaire. Therapeutic success was related to the patients' clinical characteristics. RESULTS: A significant reduction in tinnitus complaints occurred after rTMS. In the questionnaire, 40% of the patients improved by five points or more. Treatment responders were characterized by shorter duration of tinnitus complaints and no hearing impairment. CONCLUSION: Tinnitus-related neuroplastic changes might be less pronounced in patients with normal hearing and a short history of complaints. This could explain why those patients benefitted more from rTMS treatment.     

Transcranial magnetic stimulation in brain injury

Objectives

Transcranial magnetic stimulations (TMS) have been used for many years as a diagnostic tool to explore changes in cortical excitability, and more recently as a tool for therapeutic neuromodulation. We are interested in their applications following brain injury: stroke, traumatic and anoxic brain injury.

Data synthesis

Following brain injury, there is decreased cortical excitability and changes in interhemispheric interactions depending on the type, the severity, and the time-lapse between the injury and the treatment implemented. rTMS (repetitive TMS) is a therapeutic neuromodulation tool which restores the interhemispheric interactions following stroke by inhibiting the healthy cortex with frequencies ≤ 1 Hz, or by exciting the lesioned cortex with frequencies between 3 and 50 Hz. Results in motor recovery are promising and those in improving aphasia or visuospatial neglect are also encouraging. Finally, the use of TMS is mainly limited by the risk of seizure, and is therefore contraindicated for many patients.

Conclusion

TMS is a useful non-invasive brain stimulation tool to diagnose the effects of brain injury, to study the mechanisms of recovery and a non-invasive neuromodulation promising tool to influence the post-lesional recovery.     

Homeostatic metaplasticity of the motor cortex is altered during headache-free intervals in migraine with aura

Preconditioning of the human primary motor cortex (M1) with transcranial direct current stimulation (tDCS) can shape the magnitude and direction of excitability changes induced by a subsequent session of repetitive transcranial magnetic stimulation (rTMS). Here, we examined this form of metaplasticity in migraine patients with visual aura and healthy controls. In both groups, facilitatory preconditioning of left M1 with anodal tDCS increased the mean amplitudes of motor-evoked potentials (MEPs) elicited in the contralateral hand, whereas inhibitory preconditioning with cathodal tDCS produced a decrease in amplitude. Following cathodal tDCS, a short train of low-intensity 5-Hz rTMS antagonized the suppression of the mean MEP amplitude in both groups. In contrast, the homeostatic effects of 5-Hz rTMS differed between groups when rTMS was given after anodal tDCS. In controls 5-Hz rTMS induced a marked decrease in MEP amplitudes, whereas in migraineurs rTMS induced only a modest decrease in MEP amplitudes, which were still facilitated after rTMS when compared with baseline amplitudes. These findings indicate that short-term homeostatic plasticity is altered in patients with visual aura between the attacks.     

经颅磁刺激同步踏车训练在胸腰段脊髓损伤治疗中的应用

目的:探讨经颅磁刺激同步踏车训练对胸腰段脊髓损伤患者功能恢复的影响。方法:30例不完全性T10～T12脊髓损伤患者,ASIA脊髓神经功能分级均为C级,病程3～4个月,随机分为训练组和对照组。两组均接受常规康复治疗(包括物理治疗、作业治疗、理疗和梯度气压助动等),训练组比对照组仅增加经颅磁刺激同步踏车训练1个项目。治疗时间6周,比较两组治疗前后ASIA运动评分、ASIA感觉评分、脊髓损伤步行指数Ⅱ(WISCIⅡ)和功能独立性评定(FIM)情况。结果:两组患者治疗前各临床评价指标间比较均无显著性差异(P0.05)。治疗6周后,训练组ASIA运动评分、WISCIⅡ、FIM评分较治疗前均有提高,差异有显著性(P0.05);对照组FIM评分较治疗前提高,差异有显著性(P0.05),余评价指标与治疗前比较差异无显著性(P0.05)。治疗后两组间比较,经颅磁刺激同步踏车训练组ASIA运动评分、WISCIⅡ均高于对照组,差异有显著性(P0.05),ASIA感觉评分、FIM评分两组间差异无显著性(P0.05)。结论:经颅磁刺激同步踏车训练对不完全性胸腰段脊髓损伤患者运动功能恢复有一定程度的促进作用。     

Repetitive transcranial magnetic stimulation effects on brain function and cognition among elders with memory dysfunction. A randomized sham-controlled study

In the present study, we aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on memory performance and brain activity in elders presenting with subjective memory complaints and a memory performance within the low normal range. Forty participants underwent 2 functional magnetic resonance imaging (fMRI) sessions, in which they were administered 2 equivalent face-name memory tasks. Following each fMRI, subjects were asked to pair faces with their corresponding proper name. In-between, high-frequency rTMS was applied randomly using real or sham stimulation in a double-blind design. Only subjects who received active rTMS improved in associative memory significantly. This was accompanied by additional recruitment of right prefrontal and bilaterial posterior cortical regions at the second fMRI session, relative to baseline scanning. Our findings reflect a potentiality of rTMS to recruit compensatory networks, which participate during the memory-encoding process. Present results represent the first evidence that rTMS is capable of transitorily and positively influencing brain function and cognition among elders with memory complaints.     

Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study.

OBJECTIVES: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a new treatment strategy for patients with chronic tinnitus. However, functional abnormalities in tinnitus patients also involve brain structures used for attentional and emotional processing, such as the dorsolateral prefrontal cortex. Therefore, we have developed a new rTMS treatment strategy for tinnitus patients that consists of a combination of high-frequency prefrontal and low-frequency temporal rTMS. STUDY DESIGN: A total of 32 patients received either low-frequency temporal rTMS or a combination of high-frequency prefrontal and low-frequency temporal rTMS. Treatment effects were assessed with a standardized tinnitus questionnaire (TQ). RESULTS: Directly after therapy there was an improvement of the TQ-score for both groups, but no differences between groups. An evaluation after 3 months revealed a remarkable benefit from the use of combined prefrontal and temporal rTMS treatment. CONCLUSION: These results support recent data that suggest that auditory and nonauditory brain areas are involved in tinnitus pathophysiology.     

Right parietal cortex plays a critical role in change blindness

There is increasing evidence from functional magnetic resonance imaging (fMRI) that visual awareness is not only associated with activity in ventral visual cortex but also with activity in the parietal cortex. However, due to the correlational nature of neuroimaging, it remains unclear whether this parietal activity plays a causal role in awareness. In the experiment presented here we disrupted activity in right or left parietal cortex by applying repetitive transcranial magnetic stimulation (rTMS) over these areas while subjects attempted to detect changes between two images separated by a brief interval (i.e. 1-shot change detection task). We found that rTMS applied over right parietal cortex but not left parietal cortex resulted in longer latencies to detect changes and a greater rate of change blindness compared with no TMS. These results suggest that the right parietal cortex plays a critical role in conscious change detection.     

Priming of motion direction and area V5/MT: a test of perceptual memory

Presentation of supraliminal or subliminal visual stimuli that can (or cannot) be detected or identified can improve the probability of the same stimulus being detected over a subsequent period of seconds, hours or longer. The locus and nature of this perceptual priming effect was examined, using suprathreshold stimuli, in subjects who received repetitive pulse transcranial magnetic stimulation over the posterior occipital cortex, the extrastriate motion area V5/MT or the right posterior parietal cortex during the intertrial interval of a visual motion direction discrimination task. Perceptual priming observed in a control condition was abolished when area V5/MT was stimulated but was not affected by magnetic stimulation over striate or parietal sites. The effect of transcranial magnetic stimulation (TMS) on priming was specific to site (V5/MT) and to task - colour priming was unaffected by TMS over V5/MT. The results parallel, in the motion domain, recent demonstrations of the importance of macaque areas V4 and TEO for priming in the colour and form domains.     

Effects of repetitive transcranial magnetic stimulation on movement-related cortical activity in humans

Several lines of evidence suggest that low-rate repetitive transcranial magnetic stimulation (rTMS) of the motor cortex at 1 Hz reduces the excitability of the motor cortex and produces metabolic changes under and at a distance from the stimulated side. Therefore, it has been suggested that rTMS may have beneficial effects on motor performance in patients with movement disorders. However, it is still unknown in what way these effects can be produced. The aim of the present study is to investigate whether rTMS of the motor cortex (15 min at 1 Hz) is able to modify the voluntary movement related cortical activity, as reflected in the Beretischaftspotential (BP), and if these changes are functionally relevant for the final motor performance. The cortical movement-related activity in a typical BP paradigm of five healthy volunteers has been recorded using 61 scalp electrodes, while subjects performed self-paced right thumb oppositions every 8-20 s. After a basal recording, the BP was recorded in three different conditions, counterbalanced across subjects: after rTMS stimulation of the left primary motor area (M1) (15 min, 1 Hz, 10% above motor threshold), after 15 min of sham rTMS stimulation and following 15 min of voluntary movements performed with spatio-temporal characteristics similar to those induced by TMS. The tapping test was used to assess motor performance before and after each condition. Only movement-related trials with similar electromyographic (onset from muscular 'silence') and accelerometric patterns (same initial direction and similar amplitudes) were selected for computing BP waveforms. TMS- evoked and self-paced thumb movements had the same directional accelerometric pattern but different amplitudes. In all subjects, the real rTMS, but neither sham stimulation nor prolonged voluntary movements, produced a significant amplitude decrement of the negative slope of the BP; there was also a shortening of the BP onset time in four subjects. The effect was topographically restricted to cortical areas which were active in the basal condition, irrespective of the basal degree of activation at every single electrode. No changes in the tapping test occurred. These findings suggest that rTMS of the motor cortex at 1 Hz may interfere with the movement related brain activity, probably through influence on cortical inhibitory networks.     

Remediation of sleep-deprivation-induced working memory impairment with fMRI-guided transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) was applied to test the role of selected cortical regions in remediating sleep-deprivation-induced deficits in visual working memory (WM) performance. Three rTMS targets were chosen using a functional magnetic resonance imaging (fMRI)-identified network associated with sleep-deprivation-induced WM performance impairment: 2 regions from the network (upper left middle occipital gyrus and midline parietal cortex) and 1 nonnetwork region (lower left middle occipital gyrus). Fifteen participants underwent total sleep deprivation for 48 h. rTMS was applied at 5 Hz during a WM task in a within-subject sham-controlled design. The rTMS to the upper-middle occipital site resulted in a reduction of the sleep-induced reaction time deficit without a corresponding decrease in accuracy, whereas stimulation at the other sites did not. Each subject had undergone fMRI scanning while performing the task both pre- and postsleep deprivation, and the degree to which each individual activated the fMRI network was measured. The degree of performance enhancement with upper-middle occipital rTMS correlated with the degree to which each individual failed to sustain network activation. No effects were found in a subset of participants who performed the same rTMS procedure after recovering from sleep deprivation, suggesting that the performance enhancements seen following sleep deprivation were state dependent.     

Reduction of intractable deafferentation pain due to spinal cord or peripheral lesion by high-frequency repetitive transcranial magnetic stimulation of the primary motor cortex

OBJECT: The authors previously reported that navigation-guided repetitive transcranial magnetic stimulation (rTMS) of the precentral gyrus relieves deafferentation pain. Stimulation parameters were 10 trains of 10-second 5-Hz TMS pulses at 50-second intervals. In the present study, they used various stimulation frequencies and compared efficacies between two types of lesions. METHODS: Patients were divided into two groups: those with a cerebral lesion and those with a noncerebral lesion. The rTMS was applied to all the patients at frequencies of 1, 5, and 10 Hz and as a sham procedure in random order. The effect of rTMS on pain was rated by patients using a visual analog scale. RESULTS: The rTMS at frequencies of 5 and 10 Hz, compared with sham stimulation, significantly reduced pain, and the pain reduction continued for 180 minutes. A stimulation frequency of 10 Hz may be more effective than 5 Hz, and at 1 Hz was ineffective. The effect of rTMS at frequencies of 5 and 10 Hz was greater in patients with a noncerebral lesion than those with a cerebral lesion. CONCLUSIONS: High-frequency (5- or 10-Hz) rTMS of the precentral gyrus can reduce intractable deafferentation pain, but low-frequency stimulation (at 1 Hz) cannot. Patients with a noncerebral lesion are more suitable candidates for high-frequency rTMS of the precentral gyrus.     

Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses

Somatosensory and pain responses to direct intracerebral stimulations of the SII area were obtained in 14 patients referred for epilepsy surgery. Stimulations were delivered using transopercular electrodes exploring the parietal opercular cortex (SII area), the suprasylvian parietal cortex (SI area) and the insular cortex. SII responses were compared to those from adjacent SI and insular cortex. In the three areas we elicited mostly somatosensory responses, including paresthesiae, temperature and pain sensations. The rate of painful sensations (10%) was similar in SII and in the insula, while no painful sensation was evoked in SI. A few non-somatosensory responses were evoked by SII stimulation. Conversely various types of non-somatosensory responses (auditory, vegetative, vestibular, olfacto-gustatory, etc.) were evoked only by insular stimulation, confirming that SII, like SI, are mostly devoted to the processing of somatosensory inputs whereas the insular cortex is a polymodal area. We also found differences in size and lateralization of skin projection fields of evoked sensations between the three studied areas, showing a spatial resolution of the somatotopic map in SII intermediate between those found in SI and insula. This study shows the existence of three distinct somatosensory maps in the suprasylvian, opercular and insular regions, and separate pain representations in SII and insular cortex.     

Validation and the future of stimulation therapy of the primary motor cortex

The use of electrical motor cortex stimulation (EMCS) for post-stroke pain was established in Japan and has spread globally. EMCS has been used for the treatment of neuropathic pain, Parkinson's syndrome, and recovery of motor paresis. Since 2000, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of various neurological disorders. rTMS is a non-invasive method with almost no adverse effects. In the USA, rTMS of the left dorsolateral prefrontal cortex was approved for the treatment of major depression in 2008. rTMS of the primary motor cortex (M1) has been studied worldwide for the treatment of neuropathic pain, Parkinson's disease, motor paresis after stroke, and other neurological problems. New methods and devices for rTMS therapy are under development, and rTMS of the M1 is likely to be established as an effective therapy for some neurological disorders. The present review discusses EMCS and rTMS of the M1 concisely.