Differential effects of theta-gamma tACS on motor skill acquisition in young individuals and stroke survivors: A double-blind, randomized, sham-controlled study.

BACKGROUND: Theta-gamma transcranial alternating current stimulation (tACS) was recently found to enhance thumb acceleration in young, healthy participants, suggesting a potential role in facilitating motor skill acquisition. Given the relevance of motor skill acquisition in stroke rehabilitation, theta-gamma tACS may hold potential for treating stroke survivors. OBJECTIVE: We aimed to examine the effects of theta-gamma tACS on motor skill acquisition in young, healthy participants and stroke survivors. METHODS: In a pre-registered, double-blind, randomized, sham-controlled study, 78 young, healthy participants received either theta-gamma peak-coupled (TGP) tACS, theta-gamma trough-coupled (TGT) tACS or sham stimulation. 20 individuals with a chronic stroke received either TGP or sham. TACS was applied over motor cortical areas while participants performed an acceleration-dependent thumb movement task. Stroke survivors were characterized using standardized testing, with a subgroup receiving additional structural brain imaging. RESULTS: Neither TGP nor TGT tACS significantly modified general motor skill acquisition in the young, healthy cohort. In contrast, in the stroke cohort, TGP diminished motor skill acquisition compared to sham. Exploratory analyses revealed that, independent of general motor skill acquisition, healthy participants receiving TGP or TGT exhibited greater peak thumb acceleration than those receiving sham. CONCLUSION: Although theta-gamma tACS increased thumb acceleration in young, healthy participants, consistent with previous reports, it did not enhance overall motor skill acquisition in a more complex motor task. Furthermore, it even had detrimental effects on motor skill acquisition in stroke survivors.

Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex.

Magnetic resonance spectroscopy (MRS) allows measurement of neurotransmitter concentrations within a region of interest in the brain. Inter-individual variation in MRS-measured GABA levels have been related to variation in task performance in a number of regions. However, it is not clear how MRS-assessed measures of GABA relate to cortical excitability or GABAergic synaptic activity. We therefore performed two studies investigating the relationship between neurotransmitter levels as assessed by MRS and transcranial magnetic stimulation (TMS) measures of cortical excitability and GABA synaptic activity in the primary motor cortex. We present uncorrected correlations, where the P value should therefore be considered with caution. We demonstrated a correlation between cortical excitability, as assessed by the slope of the TMS input-output curve and MRS-assessed glutamate levels (r = 0.803, P = 0.015) but no clear relationship between MRS-assessed GABA levels and TMS-assessed synaptic GABA(A) activity (2.5 ms inter-stimulus interval (ISI) short-interval intracortical inhibition (SICI); Experiment 1: r = 0.33, P = 0.31; Experiment 2: r = -0.23, P = 0.46) or GABA(B) activity (long-interval intracortical inhibition (LICI); Experiment 1: r = -0.47, P = 0.51; Experiment 2: r = 0.23, P = 0.47). We demonstrated a significant correlation between MRS-assessed GABA levels and an inhibitory TMS protocol (1 ms ISI SICI) with distinct physiological underpinnings from the 2.5 ms ISI SICI (r = -0.79, P = 0.018). Interpretation of this finding is challenging as the mechanisms of 1 ms ISI SICI are not well understood, but we speculate that our results support the possibility that 1 ms ISI SICI reflects a distinct GABAergic inhibitory process, possibly that of extrasynaptic GABA tone.

Modulation of movement-associated cortical activation by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor-related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right-handed subjects performed a visually cued serial reaction time task with their right hand in a 3-T MRI scanner both before and after 10 min of 1-mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short-lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within-session linear decreases in activation occurred in all scan sessions. The after-effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between-session decrease in task-related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease.

Motor training modulates intracortical inhibitory dynamics in motor cortex during movement preparation.

BACKGROUND: The primary motor cortex (M1) has a vital role to play in the learning of novel motor skills. However, the physiological changes underpinning this learning, particularly in terms of dynamic changes during movement preparation, are incompletely understood. In particular, a substantial decrease in resting gamma-amino butyric acid (GABA) activity, i.e. a release of resting inhibition, is seen within M1 as a subject prepares to move. Although there is evidence that a decrease in resting inhibition occurs within M1 during motor learning it is not known whether the pre-movement "release" of GABAergic inhibition is modulated during skill acquisition. OBJECTIVE: Here, we investigated changes in pre-movement GABAergic inhibitory "release" during training on a motor skill task. METHODS: We studied GABAA activity using paired-pulse TMS (Short-Interval Intracortical Inhibition (SICI)) during training on a ballistic thumb abduction task, both at rest and at two time-points during movement preparation. RESULTS: Improvement in task performance was related to a later, steeper, release of inhibition during the movement preparation phase. Specifically, subjects who showed greater improvement in the task in the early stages of training showed a reduced level of GABAergic release immediately prior to movement compared with those who improved less. Later in training, subjects who performed better showed a reduction in GABAergic release early in movement preparation. CONCLUSIONS: These findings suggest that motor training is associated with maintained inhibition in motor cortex during movement preparation.

Walking performance and its recovery in chronic stroke in relation to extent of lesion overlap with the descending motor tract.

We investigated the association between the degree of lesion overlap with the corticospinal tract and walking performance before and after 4-weeks of partial body weight support (PBWS) treadmill training in 18 individuals (ten male, eight female) with a mean age 59 +/- 13 years (mean +/- SD), range 32-74 years, who were ambulant and 6 months from a subcortical ischaemic stroke. Lesion volumes were manually defined on high resolution T1-weighted 3T-MRI scans and a probabilistic map of the corticospinal tract created using diffusion tensor imaging data collected previously in healthy subjects. The percentage overlap between the lesion and the corticospinal tract was calculated for each patient. Walking performance was determined by measures of 10 m speed, spatiotemporal parameters, percentage recovery of centre of mass (CoM), walking symmetry and 2-min endurance walk prior to and following 4 weeks of treadmill training with PBWS that emphasised normal fast walking. Lesion overlap measures weakly correlated with walking performance measures. Spatiotemporal and performance measures changed in response to training, but spatial symmetry and mechanical energy recovery did not. Walking speed at entry to the study predicted change in response to training of 10 m walk time and swing time asymmetry. Age and lesion overlap did not add to prediction of outcome models. The extent of lesion overlap with the corticospinal tract was not strongly associated with either walking performance or response to gait retraining, despite the correlation of these parameters with upper limb recovery.

Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response.

Adaptation to stress requires coordinated interactions between the vascular and endocrine systems. Previously we demonstrated that restraint stress induces the expression of the major heat shock protein, HSP70, in the adrenal cortex of the rat. Here we demonstrate that restraint also induces expression of HSP70 in the vasculature. We further demonstrate that the adrenal and vascular responses are differentially regulated: the adrenal response is adrenocorticotropin dependent, whereas the vascular response is under adrenergic control. In addition, the adrenal response is restricted to members of the HSP70 gene family, whereas in vascular tissue the low molecular weight HSP, HSP27, is also induced by restraint. Further characterization of the vascular response revealed that HSP70 induction occurred in both the thoracic and abdominal aortas as well as in the vena cava. However, no HSP70 induction was apparent in the heart or in a wide variety of other tissues examined. In situ hybridization showed that the vascular expression was localized to the aortic smooth muscle cells with minimal expression in the endothelium. Induction of HSP70 mRNA in both the adrenal cortex and aorta was followed by an elevation in HSP70 protein. Maximum HSP70 protein levels were seen within 3-12 h after restraint, but declined thereafter. Stress induced HSP70 expression was dramatically reduced with age, which may explain, in part, the diminished tolerance to stress seen in elderly individuals.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.

Muscarinic acetylcholine receptor subtype mRNA expression and ligand binding in the aged rat forebrain.

Previous studies indicate that a 20-30% decline in muscarinic acetylcholine receptor binding occurs in localized areas of rat brain during aging. In this study, reduced [3H]-quinuclidinyl benzilate binding was observed in striata from 24-25-month-old rats relative to 5-6-month-old animals using homogenate binding assays. To determine if the decline in receptor concentration occurs as a result of decreased receptor synthesis, the expression of the m1, m3, and m4 muscarinic receptor mRNAs as well as [3H]-QNB binding were determined in adjacent sections of young and old male rats using in situ hybridization and in vitro receptor autoradiography respectively. A significant decline in collective muscarinic receptor binding as assessed by [3H]-QNB was observed in the caudate putamen, olfactory tubercle, nucleus accumbens, and several frontal and parietal cortical areas. The only difference observed in muscarinic mRNA expression for any of the three subtypes examined was a decline in m1 hybridization in the olfactory tubercle. The results of this study demonstrate that the regional brain areas displaying age-related decreases in receptor binding do not correlate with those areas showing a decrease in muscarinic receptor expression. Apparently, the decline in muscarinic acetylcholine receptor density with age does not result from a decline in receptor gene expression.

Induction of heat shock protein in cardiac allograft rejection--a cyclosporine-suppressible response.

The cellular response to a wide variety of stresses results in the synthesis of a family of proteins termed heat shock proteins (HSPs). To determine if acute allograft rejection could induce these proteins in a transplanted graft, we examined the HSP response to acute cardiac allograft rejection and analyzed the effect of immunosuppression upon this response. Donor hearts obtained from either Lewis (LEW) or ACI rats were heterotopically transplanted in recipient LEW rats. There were 4 experimental groups: untreated isografted (LEW to LEW) animals (n = 14), untreated allografted (ACI to LEW) animals (n = 14), cyclosporine-treated (10 mg/kg SQ/day) isografted animals (n = 12), and cyclosporine-treated allografted animals (n = 12). Animals were sacrificed on posttransplantation day 2, 4, or 6 (time of rejection for untreated allografts); n = 4-5 for each time point per group. At these times tissue obtained from the transplanted heart was examined histologically and analyzed for HSP72 by quantitative Northern and Western blots. The level of HSP72 in the untreated allografts progressively increased between 2, 4, and 6 days posttransplantation and was significantly greater than that of the untreated isografts at all time points. The HSP72 response in cyclosporine-treated allografts was significantly reduced at 4 and 6 days posttransplantation compared with the untreated allografts. In contrast, there was no difference in the HSP response in treated versus untreated isografts. Additionally, there was no difference in HSP levels in cyclosporine-treated isografts and allografts. These findings demonstrate that HSP expression in the transplanted heart correlates directly with the evolution of acute allograft rejection, and that immunosuppressive therapy inhibits the HSP response. These studies also raise the possibility of a functional role for HSPs in the allogeneic immune response.

Heat shock protein expression in human placenta and umbilical cord.

We examined the level of heat shock proteins (HSPs) present in umbilical cord vessels and placenta following delivery. A 10 cm segment of fresh umbilical cord was obtained immediately after delivery and a placental biopsy was obtained following the third stage of labor. Apgar scores, cord pHs, and pertinent histories were recorded. Tissues were prepared and analyzed for HSP mRNA by in situ hybridization, Western blot, and immunohistochemistry. Sixteen patients were studied. HSP72 mRNA was selectively expressed in the vascular smooth muscle in all cord arteries and veins. This correlated with marked expression of HSP72 protein in the vascular media. Both HSP72/73 mRNA and protein expression were noted diffusely in the placenta. HSP27 protein was highly expressed in umbilical cords with lower levels present in placentas. There were no correlations between method of delivery, gestational age, Apgar score, cord pH, or fetal outcome to the magnitude or distribution of the HSP response. This is the first demonstration of HSP expression in the human maternal-fetal circulation.

Endocrine control of stress-induced heat shock protein 70 expression in vivo.

BACKGROUND: Stress adaptation requires interactions between the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system, and a family of intracellular stress response proteins termed heat shock proteins (HSPs). These HSPs are present in every living organism and are selectively induced in the adrenal cortex and vascular smooth muscle after either surgical or restraint stress. METHODS: We perturbed the hypothalamic-pituitary-adrenal axis by implanting in the rat subcutaneous pellets containing either placebo or dexamethasone (25 mg), ovine corticotropin releasing factor (CRF, 0.5 mg), or the glucocorticoid antagonist RU 486 (5 mg) for 2 weeks before randomization to either 90 minutes of restraint stress or immediate sacrifice. The adrenal glands were weighed, trunk blood was collected for adrenocorticotropic hormone (ACTH) and corticosterone measurements, and RNA isolated from the adrenal glands and aorta was assayed for HSP70 messenger RNA expression by Northern analysis. RESULTS: Dexamethasone resulted in a twofold decrease in adrenal weight (p < 0.05). ACTH and corticosterone levels were markedly reduced in the dexamethasone treated group in the absence or presence of restraint stress. Restraint resulted in greater than 20-fold induction of HSP70 in both the adrenal gland and aorta of the placebo group compared with nonstressed controls (p < 0.01). Long-term dexamethasone treatment reduced adrenal HSP70 expression fourfold after restraint (p < 0.5), whereas neither CRF nor RU486 treatment significantly influenced the adrenal HSP70 response. Glucocorticoid manipulation with either dexamethasone or CRF did not significantly affect restraint-induced aortic HSP70 expression, whereas RU486 treatment resulted in a 50% diminution (p < 0.5) compared with placebo-treated controls. CONCLUSIONS: These data show dramatic induction of HSP70 messenger RNA expression in adrenal and aortic tissues after restraint stress. Differential organ specific HSP regulation is evidenced by the ability of the glucocorticoid dexamethasone to attenuate the adrenal but not the aortic response. The significant effect of RU486 on the aortic response suggests the possibility of vascular glucocorticoid-catecholamine interactions.

In vitro accumulation of technetium-99m-sestamibi in human parathyroid mitochondria.

BACKGROUND: Technetium-99m-sestamibi (sestamibi) is the imaging agent of choice for preoperative parathyroid localization. The subcellular localization of sestamibi uptake in enlarged parathyroid glands in patients with hyperparathyroidism has not been determined. This study investigated the mechanism of retention of sestamibi by human parathyroid tissue. METHODS: Twenty-three freshly harvested and 15 cryopreserved parathyroid glands excised from patients with primary or secondary hyperparathyroidism were analyzed for subcellular localization of Tc-99m-sestamibi. Tissues were incubated with 100 microCi of sestamibi and isolated for mitochondria by differential centrifugation, and the integrity of subcellular fractions was quantified with the mitochondrial enzyme marker, succinate dehydrogenase. RESULTS: Ninety-two percent of sestamibi activity was associated with mitochondria. Furthermore, after adding the mitochondrial uncoupler, carbonylcyanide m-chlorophenylhydrazone (CCCP), to fresh parathyroid tissues, 84.96% and 73.86% of sestamibi was released from the mitochondrial and tissue fragment components, respectively. In addition, sestamibi activity in the mitochondrial component of cryopreserved human parathyroid tissue decreased to the same amount as the CCCP-treated group. CONCLUSIONS: These data confirm that mitochondrial activity is the major component of sestamibi uptake by human parathyroid tissue in patients with hyperparathyroidism.

Adrenergic regulation of adrenal and aortic heat shock protein.

BACKGROUND: Surgical stress results in catecholamine secretion and selective induction of the major heat shock protein (HSP70) in the adrenal gland and in the vasculature. The adrenal response is cortical-specific and corticotropin-dependent. The vascular response occurs in the smooth muscle and is corticotropin-independent. We previously suggested that the vascular response was associated with adrenergic receptor stimulation. Herein, we report a series of experiments designed to test the hypothesis that aortic HSP70 messenger RNA (mRNA) induction occurs as a direct and specific response to alpha 1-adrenergic receptor stimulation. METHODS: Acute and chronic indwelling central venous catheter models were developed in the Wistar rat through which the following agents were infused: the alpha 1 agonist phenylephrine (0.14 mg/kg), the beta agonist isoproterenol (0.8 mg/kg), the alpha 1 antagonist prazosin (1 mg/kg), prazosin followed by phenylephrine, or saline solution alone. Hemodynamic responses were monitored; catecholamines were measured by high-performance liquid chromatography; 60 minutes after infusion, the animals were killed, and the adrenal glands and aortas were assayed for HSP70 mRNA expression on Northern blots. RESULTS: Alpha 1 stimulation with phenylephrine resulted in marked hypertension, a reflexive bradycardia, and marked induction of aortic HSP70 mRNA. This effect could be completely abolished when the alpha 1 antagonist prazosin was administered before phenylephrine treatment. The beta agonist isoproterenol failed to induce aortic HSP70. A significant catecholamine response only occurred after prazosin administration. CONCLUSIONS: These studies show a functional interaction between alpha 1 receptor stimulation and vascular HSP mRNA induction.

Impaired wound healing in Cushing's syndrome: the role of heat shock proteins.

BACKGROUND: Glucocorticoids impair wound healing and cause surgical morbidity. Heat shock proteins are essential to cellular stress tolerance and are associated with glucocorticoids. The adrenal heat shock protein response is under hypothalmic-pituitary-adrenal-axis control, whereas the vascular response is associated with alpha-1 receptors. Because heat shock proteins affect cellular stress responses and are under hypothalmic-pituitary-adrenal-axis control in other tissues, we postulated an association between heat shock proteins and glucocorticoids in healing wounds. METHODS: Modified Hunt-Schilling wound chambers were implanted subcutaneously in rats. They received subcutaneous time-release dexamethasone (25 mg) or placebo pellets. Wound chamber heat shock protein 25 and heat shock protein 72/73 were serially assayed for 21 days with western analysis and immunocytochemistry. RESULTS: Dexamethasone caused Cushing's syndrome with approximately 10% weekly weight-loss and adrenal atrophy. Total wound tissue decreased 90% with profound differences in molecular wound responses manifested by decreased heat shock protein 25, 72, and 73 in animals treated with dexamethasone despite equal protein loads. Furthermore, dexamethasone caused heat shock protein 72 redistribution by immunocytochemistry. CONCLUSIONS: This study represents the first description of heat shock proteins in a wound healing model and demonstrates tissue-specific decrease of heat shock proteins with glucocorticoid therapy. Thus the heat shock protein response is intimately associated with normal wound healing and is profoundly altered in subjects with Cushing's syndrome. Manipulation of this response may have clinical importance in wound healing.

Aortic crosstransplantation between young and old rats: effect upon the heat shock protein 70 stress response.

In previous studies we demonstrated that restraint, or immobilization stress, resulted in the induction of HSP70 mRNA in the vasculature of rats. This response was confined to the vascular smooth muscle, was associated with alpha 1-adrenergic receptor stimulation, and was attenuated with age. In the present study, we examined the influence of transplanting aged vessels into young animals and young vessels into aged animals to determine if this age-related diminution was due to changes intrinsic to the aorta or the result of alterations in the environment in which the aorta resides. We demonstrate that restraint-induced HSP70 expression in transplanted vessels is influenced to a greater degree by the age of the recipient than by the age of the transplanted vessel. Transplantation of aged vessels into young animals leads to preservation of the response, whereas transplantation of young vessels into aged animals leads to attenuation. These findings indicate that the environment in which the vessel resides is a major factor in determining this molecular response to stress.

Improved free musculocutaneous flap survival with induction of heat shock protein.

The cellular response to a wide variety of stresses results in the synthesis of a family of stress response proteins termed heat shock proteins. Recent studies have demonstrated that heat shock proteins produced in response to an initial stress seem to protect against subsequent unrelated stresses. Importantly, hyperthermia-induced heat shock proteins provided protection from ischemia/reperfusion injury in several organ transplantation models. We hypothesized that free musculocutaneous flap survival could be improved by enhancing the flap's tolerance to relative ischemia by the prior induction of heat shock proteins. Accordingly, we determined the heat shock protein response in skin and muscle after systemic or local heating and examined the effect on free musculocutaneous flap survival in a rat model. Free musculocutaneous flaps incorporating thigh adductor muscles and a 2 x 6-cm2 skin paddle were transplanted to the ipsilateral groin in three groups of male Wistar rats. Systemically heated rats (n = 6) were anesthetized and incubated for 30 minutes at 42 degrees C 6 hours before free musculocutaneous tissue transfer. Locally heated rats (n = 6) were anesthetized, and their donor site anterior thigh was placed for 30 minutes on a heating block set at 44 degrees C 6 hours before free tissue transfer. Control rats (n = 5) did not have heating pretreatment but underwent identical anesthesia. Animals were sacrificed on postoperative day 3, at which time skin loss (cm2) and muscle viability, quantified by nitroblue tetrazolium staining time, were assessed in a blinded fashion. The skin and muscle from the free flap were analyzed for HSP72 mRNA and protein using quantitative Northern and Western blot techniques. All free musculocutaneous flaps were viable. However, the locally and systemically heated rats demonstrated a marked improvement of skin survival, which correlated with increased skin levels of HSP72. There were no differences in nitroblue tetrazolium muscle staining times or muscle levels of HSP72 among the three groups. These findings suggest that prior heat-induced heat shock proteins result in improvement in musculocutaneous flap survival, which may have direct clinical applications, especially in high-risk patients.

The role of inhibition in human motor cortical plasticity.

Over recent years evidence from animal studies strongly suggests that a decrease in local inhibitory signaling is necessary for synaptic plasticity to occur. However, the role of GABAergic modulation in human motor plasticity is less well understood. Here, we summarize the techniques available to quantify GABA in humans, before reviewing the existing evidence for the role of inhibitory signaling in human motor plasticity. We discuss a number of important outstanding questions that remain before the role of GABAergic modulation in long-term plasticity in humans, such as that underpinning recovery after stroke, can be established.

Polarity and timing-dependent effects of transcranial direct current stimulation in explicit motor learning.

Transcranial direct current stimulation (tDCS) is attracting increasing interest as a therapeutic tool for neurorehabilitation, particularly after stroke, because of its potential to modulate local excitability and therefore promote functional plasticity. Previous studies suggest that timing is important in determining the behavioural effects of brain stimulation. Regulatory metaplastic mechanisms exist to modulate the effects of a stimulation intervention in a manner dependent on prior cortical excitability, thereby preventing destabilization of existing cortical networks. The importance of such timing dependence has not yet been fully explored for tDCS. Here, we describe the results of a series of behavioural experiments in healthy controls to determine the importance of the relative timing of tDCS for motor performance. Application of tDCS during an explicit sequence-learning task led to modulation of behaviour in a polarity specific manner: relative to sham stimulation, anodal tDCS was associated with faster learning and cathodal tDCS with slower learning. Application of tDCS prior to performance of the sequence-learning task led to slower learning after both anodal and cathodal tDCS. By contrast, regardless of the polarity of stimulation, tDCS had no significant effect on performance of a simple reaction time task. These results are consistent with the idea that anodal tDCS interacts with subsequent motor learning in a metaplastic manner and suggest that anodal stimulation modulates cortical excitability in a manner similar to motor learning.

Transcranial magnetic stimulation: from neurophysiology to pharmacology, molecular biology and genomics.

Noninvasive plasticity paradigms, both physiologically induced and artificially induced, have come into their own in the study of the effects of genetic variation on human cortical plasticity. These techniques have the singular advantage that they enable one to study the effects of genetic variation in its natural and most relevant context, that of the awake intact human cortex, in both health and disease. This review aims to introduce the currently available artificially induced plasticity paradigms, their putative mechanisms-both in the traditional language of the systems neurophysiologist and in the evolving (and perhaps more relevant for the purposes of stimulation genomics) reinterpretation in terms of molecular neurochemistry, and highlights recent studies employing these techniques by way of examples of applications.