Cerebral responses of healthy humans to rhythmic transcranial magnetic stimulation of different intensities

The effect of rhythmic transcranial magnetic stimulation (rTMS) of different intensities (single superthreshold rTMS more intense than 1.2 T and subthreshold one with an intensity of 70–80% of the motor threshold) of sagittal premotor cortical areas on the human functional activity was estimated in eight volunteers on the basis of combined EEG, neuropsychological, and hemodynamic examinations. The objectives of the study included the selection of the frequency of activating stimulation and revision of the objective EEG criteria of rTMS efficiency. It has been demonstrated that analysis of the EEG response to photostimulation at different frequencies is efficient in selecting the rTMS frequency. The EEG coherence is one of the most informative characteristics of the rTMS effect on central neurodynamics. The functional effects of stimulation (activating or inhibitory) have been shown to depend on the initial level of intercentral coherent relationships It has been found that rTMS of the sagittal premotor cortex causes definite changes in the functional activity of a healthy brain different from those caused by placebo. These changes are greater in the left hemisphere (in the form of intrahemispheric changes in coherence and depend on the stimulation intensity (superor subthreshold) and the initial state. The vascular factor has been shown to play an important role in the formation of cerebral responses to rTMS.     

The reflection of compensation processes in the structure of the EEG spatial-temporal relationships in patients with disordered brain regulatory mechanisms]

Studies of intercentral relations of electrical activity in the cerebral cortex of the patients with hypophysis tumours under the conditions of chronic (before operation) and acute (after tumour ablation, early post-operative period) influence of the focus on the regulatory brain systems allowed to reveal definite changes of spectral-coherent EEG characteristics, reflecting the functional state of the cerebral adaptive-compensatory apparatus. It has been shown that reciprocal character of changes of various forms of the brain electrical activity and their intercentral relations is one of manifestations of development of the processes of cerebral compensation. At the same time, global fall of the EEG intercentral relations indicating the disintegration of the cerebral functional connections, reflects a loss of CNS compensatory mechanisms. The revealed EEG-characteristics at the present time are applied in Burdenko Institute of Neurosurgery for diagnostic-prognostic estimation of the brain functional state in patients during pre- and post-operative period.     

Intracerebral EEG functioning as a reflexion of the systemic brain organization in norm and pathology

The authors summarized the EEG findings and defined the nature of intercentral EEG relationships in different functional states of healthy subjects and patients with organic cerebral pathology based on coherence analysis. The EEG features typical of healthy subjects were identified: an anterior-posterior gradient of the mean coherence and the character of cortical-subcortical relationships in the anterior cerebral structures. Right- and lefthanded subjects showed the frequency and regional differences in EEG coherence, which reflected, mainly, specific intracortical relationships. Development and regression of pathologic signs in right- and lefthanded patients with organic brain lesions are thought to be determined by these differences. As distinct from cortical pathology, lesions of regulatory structures (diencephalic, brainstem, and limbic) were shown to produce more diffuse changes in intercentral relationships with a tendency to reciprocity. Intercentral relations, including their interhemispheric differences, varied with changes in the functional state of healthy subjects (increase and decrease in the level of functioning). A certain time course of changes in intercentral relationships was also revealed in patients with organic brain lesions during recovery of their consciousness and mental activity. Changes in the dominance of activity of individual regulatory structures are considered to be one of the most important factors that determine the dynamic character of EEG coherence.     

The significance of interhemispheric asymmetry in the development of compensatory processes in the human brain

For more precise definition of the role of hemispheric interconnections in mechanisms of human CNS compensation the intercentral relations of the electrical activity of the left and right cerebral hemispheres were studied on physiological model of focal interhemispheric asymmetry. Spectral-coherent EEG characteristics of 36 patients with tumoral damage of one hemisphere were studied in condition of chronic (prior to operation) and acute (early terms of postoperative period) brain decompensation. In was shown that the reorganization of the structure of the EEG intercentral relations correlated with definite stages of CNS compensatory processes and that the character of hemispheric interconnections depended on the lateralization of the damage focus. The primary role was revealed of the degree of the left (dominant) hemisphere preservation in restoration of normal pattern of the interhemispheric asymmetry of the coherence of human brain electrical processes.     

Brain lipid changes after repetitive transcranial magnetic stimulation: potential links to therapeutic effects?

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used in the management of neurologic disorders such as depression and chronic pain, but little is known about how it could affect brain lipids, which play important roles in membrane structure and cellular functions. The present study was carried out to examine the effects of rTMS on brain lipids at the individual molecular species level using the novel technique of lipidomics. Rats were subjected to high frequency (15 Hz) stimulation of the left hemisphere with different intensities and pulses of rTMS. The prefrontal cortex, hippocampus and striatum were harvested 1 week after rTMS and lipid profiles analyzed by tandem mass spectrometry. rTMS resulted in changes mainly in the prefrontal cortex. There were significant alterations in plasmalogen phosphatidylethanolamines, phosphatidylcholines, and increases in sulfated galactosylceramides or sulfatides. Plasmalogen species with long chain polyunsaturated fatty acids (PUFAs) showed decrease in abundance together with corresponding increase in lysophospholipid species suggesting endogenous release of long chain fatty acids such as docosahexaenoic acid (DHA) in brain tissue. The hippocampus showed no significant changes, whilst changes in the striatum were often opposite to that of the prefrontal cortex. It is postulated that changes in brain lipids may underlie some of the clinical effects of rTMS.     

The Effect of 10 Hz Repetitive Transcranial Magnetic Stimulation of Posterior Parietal Cortex on Visual Attention

Repetitive transcranial magnetic stimulation (rTMS) of the posterior parietal cortex (PPC) at frequencies lower than 5 Hz transiently inhibits the stimulated area. In healthy participants, such a protocol can induce a transient attentional bias to the visual hemifield ipsilateral to the stimulated hemisphere. This bias might be due to a relatively less active stimulated hemisphere and a relatively more active unstimulated hemisphere. In a previous study, Jin and Hilgetag (2008) tried to switch the attention bias from the hemifield ipsilateral to the hemifield contralateral to the stimulated hemisphere by applying high frequency rTMS. High frequency rTMS has been shown to excite, rather than inhibit, the stimulated brain area. However, the bias to the ipsilateral hemifield was still present. The participants’ performance decreased when stimuli were presented in the hemifield contralateral to the stimulation site. In the present study we tested if this unexpected result was related to the fact that participants were passively resting during stimulation rather than performing a task. Using a fully crossed factorial design, we compared the effects of high frequency rTMS applied during a visual detection task and high frequency rTMS during passive rest on the subsequent offline performance in the same detection task. Our results were mixed. After sham stimulation, performance was better after rest than after task. After active 10 Hz rTMS, participants’ performance was overall better after task than after rest. However, this effect did not reach statistical significance. The comparison of performance after rTMS with task and performance after sham stimulation with task showed that 10 Hz stimulation significantly improved performance in the whole visual field. Thus, although we found a trend to better performance after rTMS with task than after rTMS during rest, we could not reject the hypothesis that high frequency rTMS with task and high frequency rTMS during rest equally affect performance.     

Intercentral EEG relationships in regressive and chronic post-traumatic Korsakoff syndrome.]

Dynamic EEG study of patients with posttraumatic Korsakoff's syndrome (KS) with the application of complex analysis methods revealed a complicated pathological structure of the intercentral relations of cortical electrical activity. The interhemispheric EEG coherence between symmetrical frontal cortical areas are sharply reduced, while the intrahemispheric coherence are increased in comparison with the normal values. The proposed technique of segregation of statistically homogeneous spectro-coherent characteristics made it possible to reveal the earlier intercentral EEG relations formed by stable and variable coherence spectra. The structure formed by the stable and variable coherence spectra in KS differs from that reflected in the mean coherence levels. During the KS regression, the EEG coherence between the right and left frontal areas increased to the normal level, and the variable spectra are revealed. In the chronic KS syndrome, the pathological intercentral relations persist, while the variable relations in the frontal areas are absent. A reduction of pathologically decreased intrahemispheric coherence selectively revealed in the right hemisphere during the KS regression and formation of variable relations in this hemisphere point to a leading role of the right hemisphere in development of compensatory processes in KS. The reciprocal relations between the intra- and interhemispheric coherence and coherence dynamics in the theta rhythm suggest that pathological activity in the basal diencephalic structures plays an important role in formation of the pathological EEG pattern in KS.     

Optimal structure of the connections of the electrical processes in the human cerebral cortex and its disorders in changes of state

In this paper the data are analyzed on the human EEG investigation. Significance is shown of parameters of correlative and spectral-coherent EEG functions for the estimation of the brain functional state of healthy people and patients with local cerebral lesions. In the norm, the parameter of the mean coherence is stable, its characteristics correspond to the optimum cortical tone, the most favourable for the performance of the cortical functions. In healthy people unstable, individual, different in different cortical areas changes of the spectrum details, coherence and phases reflect local processes, taking place at the optimum mean level of the coherence and form the cortical mosaic. These two sides of the intercentral relations of the electrical processes (optimum level of coherence and dynamic mosaic of connections of separate rhythms) reflect the most favourable conditions of the nervous processes development. In the brain pathology, different forms are noted of deviations from the system of intercentral relations and levels of coherence of cortical electrical processes.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Changes in the brain spontaneous bioelectrical activity during transcranial electrical and electromagnetic stimulation

In order to study systemic brain reactions on transcranial electrical or electromagnetic medical stimulation and specify the neurophysiological criteria of its efficiency, comparative clinical and experimental examination was performed with the analysis of spontaneous bioelectric activity and behavioral or clinical parameters. We examined 6 patients with prolonged posttraumatic unconsciousness states treated with electrical stimulation and 17 intact Wistar rats subjected to electromagnetic stimulation of the brain. The effect of the transcranial stimulation was shown to depend on the initial level of the intercentral interactions of brain bioelectrical activity, estimated by the EEG coherence. Hypersynchronization of biopotentials as the main element of the brain reactivity can be the most useful for the rehabilitation of patients with cerebral pathology in cases of initially lowered level of the intercentral interactions in the absence of pathologically strengthened functional connections.     

Formation of the functional organization of the cerebral cortex at rest in young schoolchildren varying in the maturity of cerebral regulatory systems: II. Analysis of EEG α-rhythm coherence

Coherence (COH) of rhythmic components of the EEG α rhythm at rest was analyzed to demonstrate that the maturation of deep regulatory systems (RSs) of the brain at different levels substantially affected the functional organization of the cerebral cortex and the time course of the formation of intercentral connections in young schoolchildren. The specific effect of fronto-thalamic regulatory system immaturity (FRSI) was a decrease in the α-rhythm COH predominantly in neighboring left-hemispheric derivations of foci in the anterior temporal area. A deficit of nonspecific activation had the strongest effect on the α-rhythm integration of right-hemispheric areas, although this effect was less distinct than that of FRSI and remained only as a tendency by the age of nine to ten years. Children with normal and functionally immature cerebral RSs differed from each other with respect to age-related changes in the corticocortical connections, especially in the left hemisphere. In the norm, intense growth of functional connections in the left hemisphere ceased in the period between seven to eight and nine to ten years of age; in contrast, children with RS immaturity exhibited a trend towards an increasingly greater amount of these connections in both hemispheres, which, apparently, corresponded to an earlier stage of ontogeny.     

The motor dominant in man]

Study of the motor dominant in man has shown that in aftereffect of rhythmic electrocutaneous stimulation of hand, a latent focus of excitation is formed in the CNS. When using sensory stimuli (light, sound) and also stimuli, addressed to the second signal system, a hand motor reaction appears in the rhythm of earlier electrocutaneous stimulation, what testifies to preservation of rhythmic nature of excitation in the dominant focus. Summation process in the dominant focus is not reflected in human consciousness. Study of the brain biopotentials has shown that at formation of human motor dominant, typical changes of spectral-coherent characteristics of the neocortex electrical activity appear: within the "dominant" hemisphere, the spectrum power, increases in the range of low frequencies; highly coherent connections of electrical processes appear in the delta-range of the frontal-parietal area at conjugate decrease of combination of processes in the parietal-occipital area of the cerebral cortex. Formation of the dominant focus in one hemisphere causes general reconstruction of the structure of intercentral relations of both hemispheres electrical activity.     

rTMS Induced Tinnitus Relief Is Related to an Increase in Auditory Cortical Alpha Activity

Chronic tinnitus, the continuous perception of a phantom sound, is a highly prevalent audiological symptom. A promising approach for the treatment of tinnitus is repetitive transcranial magnetic stimulation (rTMS) as this directly affects tinnitus-related brain activity. Several studies indeed show tinnitus relief after rTMS, however effects are moderate and vary strongly across patients. This may be due to a lack of knowledge regarding how rTMS affects oscillatory activity in tinnitus sufferers and which modulations are associated with tinnitus relief. In the present study we examined the effects of five different stimulation protocols (including sham) by measuring tinnitus loudness and tinnitus-related brain activity with Magnetoencephalography before and after rTMS. Changes in oscillatory activity were analysed for the stimulated auditory cortex as well as for the entire brain regarding certain frequency bands of interest (delta, theta, alpha, gamma). In line with the literature the effects of rTMS on tinnitus loudness varied strongly across patients. This variability was also reflected in the rTMS effects on oscillatory activity. Importantly, strong reductions in tinnitus loudness were associated with increases in alpha power in the stimulated auditory cortex, while an unspecific decrease in gamma and alpha power, particularly in left frontal regions, was linked to an increase in tinnitus loudness. The identification of alpha power increase as main correlate for tinnitus reduction sheds further light on the pathophysiology of tinnitus. This will hopefully stimulate the development of more effective therapy approaches.     

Post-radiation effect on the interhemispheric asymmetry in EEG and thermography characteristics

Complex analysis of EEG and thermographic parameters carried out in 10 healthy subjects and 34 patients, Chernobyl clean-up participants revealed a correlation between EEG and brain temperature changes in the baseline state and during mental arithmetic. During cognitive activity the maximal increase in the average EEG coherence and temperature shifts in healthy subjects were observed in the left frontotemporal and right parietotemporal areas. In patients changes in both parameters under study were most pronounced, the interhemispheric relations were impaired. The visual analysis revealed "flat" and "hypersynchronous" EEG types in patients. The dominant pathologic activity in the betal range indicative of mediobasal and oral brainstem lesions was characteristic of the flat EEG. This type of activity was observed in 60% of patients. In these cases, a general decrease in EEG coherence and temperature was most pronounced in the left hemisphere. The hypersynchronou EEG type (40% patients) was characterized by paroxysmal activity in the theta and alpha ranges suggesting diencephalic brain lesions. In these cases, EEG coherence and temperature were more variable; changes in the right hemisphere were significant, be it increase or decrease. Our complex approach to investigation of brain activity in different aspects seems to be promising in estimation of the brain functional state both in healthy persons and patients in remote terms after exposure to radiation. The specific hemispheric temperature changes revealed in Chernobyl patients especially during cognitive activity can be the sequels of postradiation disorders of vascular neuro-circulation. The EEG findings suggest subcortical disorders at different levels (diencephalic or brainstem) and functional failure of the right or left hemispheres in remote terms after exposure to radiation.     

On Disturbances of Interhemispheric Interaction in Psychopathologic States (Development of Ideas of L.Ya. Balonov and V.L. Deglin)

The current state of the problem of changes of brain functional asymmetry in psychopathology is reviewed from the point of view of disorders of interhemispheric interaction as the main chain in genesis of affective disorders and schizophrenia. Based on studies of individual activation of the left and right hemispheres as well as on evaluation of cognitive activity, it is shown that psychopathology is accompanied by a disorder of hemispheric interaction with shift of the interhemispheric activation balance towards the right hemisphere in depression and towards the left hemisphere in maniacal states and paranoid schizophrenia. Changes of the activation balance lead to disorder of cognitive activity and human adaptation in the environment. A conclusion is made that disinhibition of subcortical and brainstem structures in psychoses occurs not only vertically, but also horizontally, when the complementary and superpositional interaction of hemispheres shifts to the evolutionary earlier reciprocal type of interaction with domination of cognitive functions of the right hemisphere in depression and of the left hemisphere in the maniacal state and schizophrenia.     

The Effects of Different Repetitive Transcranial Magnetic Stimulation (rTMS) Protocols on Cortical Gene Expression in a Rat Model of Cerebral Ischemic-Reperfusion Injury

Although repetitive Transcranial Magnetic Stimulation (rTMS) in treatment of stroke in humans has been explored over the past decade the data remain controversial in terms of optimal stimulation parameters and the mechanisms of rTMS long-term effects. This study aimed to explore the potential of different rTMS protocols to induce changes in gene expression in rat cortices after acute ischemic-reperfusion brain injury. The stroke was induced by middle cerebral artery occlusion (MCAO) with subsequent reperfusion. Changes in the expression of 96 genes were examined using low-density expression arrays after MCAO alone and after MCAO combined with 1Hz, 5Hz, continuous (cTBS) and intermittent (iTBS) theta-burst rTMS. rTMS over the lesioned hemisphere was given for two weeks (with a 2-day pause) in a single daily session and a total of 2400 pulses. MCAO alone induced significant upregulation in the expression of 44 genes and downregulation in 10. Two weeks of iTBS induced significant increase in the expression of 52 genes. There were no downregulated genes. 1Hz and 5Hz had no significant effects on gene expression, while cTBS effects were negligible. Upregulated genes included those involved in angiogenesis, inflammation, injury response and cellular repair, structural remodeling, neuroprotection, neurotransmission and neuronal plasticity. The results show that long-term rTMS in acute ischemic-reperfusion brain injury induces complex changes in gene expression that span multiple pathways, which generally promote the recovery. They also demonstrate that induced changes primarily depend on the rTMS frequency (1Hz and 5Hz vs. iTBS) and pattern (cTBS vs. iTBS). The results further underlines the premise that one of the benefits of rTMS application in stroke may be to prime the brain, enhancing its potential to cope with the injury and to rewire. This could further augment its potential to favorably respond to rehabilitation, and to restore some of the loss functions.     

What happens when we get angry? Hormonal, cardiovascular and asymmetrical brain responses

This study aimed to evaluate neuroendocrine and cardiovascular responses together with changes in brain asymmetry following an anger mood induction laboratory task. Previous research has shown an increase in heart rate and blood pressure when anger is experienced. Increased testosterone and decreased cortisol in response to anger and aggressive behavior have also been reported. With regard to asymmetrical frontal brain activity and emotion, the valence model links negative affect (as anger) to the right hemisphere while the motivational direction model links approach-related emotions (as anger) to the left hemisphere. From the subjective perception and from the neuroendocrine and cardiovascular response of the subjects, we can conclude that the self-referent statement anger induction method by Engebretson et al. (1999) was able to generate an experience of an anger affect in 30 healthy men. Another question was to analyze the consequences of that experience upon perceptual asymmetry when measured with a non-emotional laterality task. Regarding dichotic listening, an enhanced REA (right ear advantage) was observed after anger which indicates greater left hemisphere activity, supporting the motivational direction model.     

EEG dynamics during conditioning in symmetrical neocortical regions in dogs

Changes in the frequency of the EEG recorded in symmetrical areas of the frontal and auditory cortices were studied during food conditioning in four dogs. Spectral-correlation analysis was applied. EEG frequency changes depended on individual features of the animals, frequency band, and stage of conditioning. In the beta-2-range, the EEG frequency increased in comparison to the initial values in all the dogs. In three dogs, the EEG frequency in the beta range decreased in the frontal and increased in the auditory cortex. Heterodirectional frequency changes led to the development of the functional interhemispheric EEG asymmetry that was partial and dynamic. At the initial stages of conditioning higher activity was in the left hemisphere, later on asymmetry was absent (or activity of the right hemisphere predominated).     

Stimulation of the left dorsolateral prefrontal cortex with slow rTMS enhances verbal memory formation

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. We here present an incidental finding from a simultaneous EEG-TMS experiment as well as a replication of this unexpected effect. Our results reveal that stimulating the left dorsolateral prefrontal cortex (DLPFC) with slow repetitive transcranial magnetic stimulation (rTMS) leads to enhanced word memory performance. A total of 40 healthy human participants engaged in a list learning paradigm. Half of the participants (N = 20) received 1 Hz rTMS to the left DLPFC, while the other half (N = 20) received 1 Hz rTMS to the vertex and served as a control group. Participants receiving left DLPFC stimulation demonstrated enhanced memory performance compared to the control group. This effect was replicated in a within-subjects experiment where 24 participants received 1 Hz rTMS to the left DLPFC and vertex. In this second experiment, DLPFC stimulation also induced better memory performance compared to vertex stimulation. In addition to these behavioural effects, we found that 1 Hz rTMS to DLPFC induced stronger beta power modulation in posterior areas, a state that is known to be beneficial for memory encoding. Further analysis indicated that beta modulations did not have an oscillatory origin. Instead, the observed beta modulations were a result of a spectral tilt, suggesting inhibition of these parietal regions. These results show that applying 1 Hz rTMS to DLPFC, an area involved in episodic memory formation, improves memory performance via modulating neural activity in parietal regions.

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. An incidental finding from a simultaneous EEG-TMS experiment reveals that applying 1-Hz repetitive transcranial magnetic stimulation to this area of the brain improves memory performance by modulating neural activity in parietal regions.     

EEG pattern as an instrument for evaluation of neurophysiological mechanisms underlying adaptation disorders

The method of statistical evaluation of probable interaction between the main constituents of bioelectrical activity of the brain (BEA) enables to reveal the character of intercentral relations both under normal conditions and at adaptation disorders of different severance. Several types of statistic interactions have been revealed between EEG components (SSIC) correlating with normal interrelations between cortex and subcortex, level of preferential involvement of non-specific brain formations (cortex, thalamic, hypothalamic and brain-stem) into the process, and the degree of instability of neuro-dynamic processes. The findings obtained have shown the degree of expression of adaptation disorders to be connected with gradual destruction of "functional nuclear" within alpha-range, amplification of statistical interrelations with beta-EEG and teta-EEG components and formation of pathological nuclear structures within the ranges aforesaid.