Probing Our Built-in Calculator: A Systematic Narrative Review of Noninvasive Brain Stimulation Studies on Arithmetic Operation-Related Brain Areas.

This systematic review presented a comprehensive survey of studies that applied transcranial magnetic stimulation and transcranial electrical stimulation to parietal and nonparietal areas to examine the neural basis of symbolic arithmetic processing. All findings were compiled with regard to the three assumptions of the triple-code model (TCM) of number processing. Thirty-seven eligible manuscripts were identified for review (33 with healthy participants and 4 with patients). Their results are broadly consistent with the first assumption of the TCM that intraparietal sulcus both hold a magnitude code and engage in operations requiring numerical manipulations such as subtraction. However, largely heterogeneous results conflicted with the second assumption of the TCM that the left angular gyrus subserves arithmetic fact retrieval, such as the retrieval of rote-learned multiplication results. Support is also limited for the third assumption of the TCM, namely, that the posterior superior parietal lobule engages in spatial operations on the mental number line. Furthermore, results from the stimulation of brain areas outside of those postulated by the TCM show that the bilateral supramarginal gyrus is involved in online calculation and retrieval, the left temporal cortex in retrieval, and the bilateral dorsolateral prefrontal cortex and cerebellum in online calculation of cognitively demanding arithmetic problems. The overall results indicate that multiple cortical areas subserve arithmetic skills.

Twenty-Three Months Repetitive Transcranial Magnetic Stimulation of the Primary Motor Cortex for Refractory Trigeminal Neuralgia: A Single-Case Study.

Treatment refractory or recurrent trigeminal neuralgia (TN) is a severe chronic pain illness. Single-session repetitive transcranial magnetic stimulation (rTMS) has been shown to elicit analgesic effects in several craniofacial pain syndromes, including TN. However, the safety and long-term effect of multi-session rTMS for TN have yet to be fully explored. In this study, we present a case of a patient with medical treatment-refractory TN after microvascular decompression. The patient volunteered to undergo 73 sessions of 10 Hz rTMS over 23 months. Neurovagination was used for precise localization and stimulation of the hand and face representation at the left motor cortex. The numeric pain intensity scores derived using the visual analog scale served as a daily index of treatment efficacy. The patient experienced a significant weekly reduction in pain scores, cumulating in 70.89% overall pain relief. The medication dosages were reduced and then discontinued toward the end of the intervention period. No severe adverse events were reported. From our results, we can conclude that the longitudinal multi-session application of rTMS over the hand and face area of M1 is a safe and effective method for producing long-lasting pain relief in TN. Using rTMS may thus prove helpful as an adjunct to conventional methods for treating pain in TN.

Reduced Cerebellar Brain Inhibition and Vibrotactile Perception in Response to Mechanical Hand Stimulation at Flutter Frequency.

The cerebellum is traditionally considered a movement control structure because of its established afferent and efferent anatomical and functional connections with the motor cortex. In the last decade, studies also proposed its involvement in perception, particularly somatosensory acquisition and prediction of the sensory consequences of movement. However, compared to its role in motor control, the cerebellum's specific role or modulatory influence on other brain areas involved in sensory perception, specifically the primary sensorimotor cortex, is less clear. In the present study, we explored whether peripherally applied vibrotactile stimuli at flutter frequency affect functional cerebello-cortical connections. In 17 healthy volunteers, changes in cerebellar brain inhibition (CBI) and vibration perception threshold (VPT) were measured before and after a 20-min right hand mechanical stimulation at 25 Hz. 5 Hz mechanical stimulation of the right foot served as an active control condition. Performance in a Grooved Pegboard test (GPT) was also measured to assess stimulation's impact on motor performance. Hand stimulation caused a reduction in CBI (13.16%) and increased VPT but had no specific effect on GPT performance, while foot stimulation had no significant effect on all measures. The result added evidence to the functional connections between the cerebellum and primary motor cortex, as shown by CBI reduction. Meanwhile, the parallel increase in VPT indirectly suggests that the cerebellum influences the processing of vibrotactile stimulus through motor-sensory interactions.

Modulation of proper name recall by transcranial direct current stimulation of the anterior temporal lobes.

We often fail to recall another person's name. Proper names might be more difficult to memorize and retrieve than other pieces of knowledge, such as one's profession because they are processed differently in the brain. Neuroimaging and neuropsychological studies associate the bilateral anterior temporal lobes (ATL) in the retrieval of proper names and other person-related knowledge. Specifically, recalling a person's name is thought to be supported by the left ATL, whereas recalling specific information such as a person's occupation is suggested to be subserved by the right ATL. To clarify and further explore the causal relationship between both ATLs and proper name retrieval, we stimulated these regions with anodal, cathodal and sham transcranial direct current stimulation (tDCS) while the participants memorized surnames (e.g., Mr. Baker) and professions (e.g., baker) presented with a person's face. The participants were then later asked to recall the surname and the profession. Left ATL anodal stimulation resulted in higher intrusion errors for surnames than sham, whereas right ATL anodal stimulation resulted in higher overall intrusion errors, both, surnames and professions, compared to cathodal stimulation. Cathodal stimulation of the left and right ATL had no significant effect on surname and profession recall. The results indicate that the left ATL plays a role in recalling proper names. On the other hand, the specific role of the right ATL remaines to be explored.

Comparing the Impact of Multi-Session Left Dorsolateral Prefrontal and Primary Motor Cortex Neuronavigated Repetitive Transcranial Magnetic Stimulation (nrTMS) on Chronic Pain Patients.

Repetitive transcranial stimulation (rTMS) has been shown to produce an analgesic effect and therefore has a potential for treating chronic refractory pain. However, previous studies used various stimulation parameters (including cortical targets), and the best stimulation protocol is not yet identified. The present study investigated the effects of multi-session 20 Hz (2000 pulses) and 5 Hz (1800 pulses) rTMS stimulation of left motor cortex (M1-group) and left dorsolateral prefrontal cortex (DLPFC-group), respectively. The M1-group (n = 9) and DLPFC-group (n = 7) completed 13 sessions of neuronavigated stimulation, while a Sham-group (n = 8) completed seven sessions of placebo stimulation. The outcome was measured using the German Pain Questionnaire (GPQ), Depression, Anxiety and Stress Scale (DASS), and SF-12 questionnaire. Pain perception significantly decreased in the DLPFC-group (38.17%) compared to the M1-group (56.11%) (p ≤ 0.001) on the later sessions. Health-related quality of life also improved in the DLPFC-group (40.47) compared to the Sham-group (35.06) (p = 0.016), and mental composite summary (p = 0.001) in the DLPFC-group (49.12) compared to M1-group (39.46). Stimulation of the left DLPFC resulted in pain relief, while M1 stimulation was not effective. Nonetheless, further studies are needed to identify optimal cortical target sites and stimulation parameters.

Inhibitory Effect of Apomorphine on Focal and Nonfocal Plasticity in the Human Motor Cortex.

Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.

Visual Cortex Transcranial Direct Current Stimulation for Proliferative Diabetic Retinopathy Patients: A Double-Blinded Randomized Exploratory Trial.

Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes. PDR-related retinal hemorrhages often lead to severe vision loss. The main goals of management are to prevent visual impairment progression and improve residual vision. We explored the potential of transcranial direct current stimulation (tDCS) to enhance residual vision. tDCS applied to the primary visual cortex (V1) may improve visual input processing from PDR patients' retinas. Eleven PDR patients received cathodal tDCS stimulation of V1 (1 mA for 10 min), and another eleven patients received sham stimulation (1 mA for 30 s). Visual acuity (logarithm of the minimum angle of resolution (LogMAR) scores) and number acuity (reaction times (RTs) and accuracy rates (ARs)) were measured before and immediately after stimulation. The LogMAR scores and the RTs of patients who received cathodal tDCS decreased significantly after stimulation. Cathodal tDCS has no significant effect on ARs. There were no significant changes in the LogMAR scores, RTs, and ARs of PDR patients who received sham stimulation. The results are compatible with our proposal that neuronal noise aggravates impaired visual function in PDR. The therapeutic effect indicates the potential of tDCS as a safe and effective vision rehabilitation tool for PDR patients.

Dissociating Arithmetic Operations in the Parietal Cortex Using 1 Hz Repetitive Transcranial Magnetic Stimulation: The Importance of Strategy Use.

The triple-code model (TCM) of number processing suggests the involvement of distinct parietal cortex areas in arithmetic operations: the bilateral horizontal segment of the intraparietal sulcus (hIPS) for arithmetic operations that require the manipulation of numerical quantities (e.g., subtraction) and the left angular gyrus (AG) for arithmetic operations that require the retrieval of answers from long-term memory (e.g., multiplication). Although neuropsychological, neuroimaging, and brain stimulation studies suggest the dissociation of these operations into distinct parietal cortex areas, the role of strategy (online calculation vs. retrieval) is not yet fully established. In the present study, we further explored the causal involvement of the left AG for multiplication and left hIPS for subtraction using a neuronavigated repetitive transcranial magnetic stimulation (rTMS) paradigm. Stimulation sites were determined based on an fMRI experiment using the same tasks. To account for the effect of strategy, participants were asked whether they used retrieval or calculation for each individual problem. We predicted that the stimulation of the left AG would selectively disrupt the retrieval of the solution to multiplication problems. On the other hand, stimulation of the left hIPS should selectively disrupt subtraction. Our results revealed that left AG stimulation was detrimental to the retrieval and online calculation of solutions for multiplication problems, as well as, the retrieval (but not online calculation) of the solutions to subtraction problems. In contrast, left hIPS stimulation had no detrimental effect on both operations regardless of strategy.

Age-Dependent Effect of Transcranial Alternating Current Stimulation on Motor Skill Consolidation.

Transcranial alternating current stimulation (tACS) is the application of subthreshold, sinusoidal current to modulate ongoing brain rhythms related to sensory, motor and cognitive processes. Electrophysiological studies suggested that the effect of tACS applied at an alpha frequency (8-12 Hz) was state-dependent. The effects of tACS, that is, an increase in parieto-occipital electroencephalography (EEG) alpha power and magnetoencephalography (MEG) phase coherence, was only observed when the eyes were open (low alpha power) and not when the eyes were closed (high alpha power). This state-dependency of the effects of alpha tACS might extend to the aging brain characterized by general slowing and decrease in spectral power of the alpha rhythm. We additionally hypothesized that tACS will influence the motor cortex, which is involved in motor skill learning and consolidation. A group of young and old healthy adults performed a serial reaction time task (SRTT) with their right hand before and after the tACS stimulation. Each participant underwent three sessions of stimulation: sham, stimulation applied at the individual participant's alpha peak frequency or individual alpha peak frequency (iAPF; α-tACS) and stimulation with iAPF plus 2 Hz (α2-tACS) to the left motor cortex for 10 min (1.5 mA). We measured the effect of stimulation on general motor skill (GMS) and sequence-specific skill (SS) consolidation. We found that α-tACS and α2-tACS improved GMS and SS consolidation in the old group. In contrast, α-tACS minimally improved GMS consolidation but impaired SS consolidation in the young group. On the other hand, α2-tACS was detrimental to the consolidation of both skills in the young group. Our results suggest that individuals with aberrant alpha rhythm such as the elderly could benefit more from tACS stimulation, whereas for young healthy individuals with intact alpha rhythm the stimulation could be detrimental.

Impact of Priming on Effectiveness of TMS in Detecting Language-eloquent Brain Areas in Tumor Patients.

BACKGROUND AND STUDY AIMS: Language is characteristically human, and preserving it is critical when resecting tumors in language-eloquent brain areas. Navigated repetitive transcranial magnetic stimulation (nrTMS) has been used in recent years as a noninvasive technique to identify preoperatively the language-eloquent cortical areas in tumor patients. An important objective is to increase the sensitivity and specificity of nrTMS in detecting language-related areas and increase the positive correlation of its results to that of intraoperative direct cortical stimulation (DCS). Although the technical aspects of the procedure have received enormous interest, factors related to the targeted cortical area such as previous cortical history or activity have been neglected. Therefore, the present study explores the impact of previous cortical history or activity on the effectiveness of a subsequent nrTMS mapping paradigm. MATERIALS AND METHODS: Twelve right-handed patients with a left hemispheric glioma underwent presurgical nrTMS language mapping and intraoperative language mapping with DCS. nrTMS was performed using a continuous theta burst stimulation paradigm to inhibit possible language relevant areas in the vicinity of the tumor, determined anatomically or based on functional magnetic resonance imaging hotspots. The nrTMS was applied in two separate sessions. One of the sessions randomly included a priming paradigm to precondition the targeted cortical areas. RESULTS: Priming stimulation decreased the error detection of the subsequent nrTMS mapping paradigm. This effect was more robust on major types of errors such as speech arrest and hesitation. CONCLUSION: Prior cortical activity as induced by the priming stimulation has a profound impact on the responsiveness to the nrTMS mapping paradigm. Our findings further showed that metaplasticity, a type of homeostatic plastic process, could be elicited even in cortical areas affected by a growing tumor.

The effects of transcranial alternating current stimulation (tACS) at individual alpha peak frequency (iAPF) on motor cortex excitability in young and elderly adults.

Transcranial alternating current stimulation (tACS) can modulate brain oscillations, cortical excitability and behaviour. In aging, the decrease in EEG alpha activity (8-12 Hz) in the parieto-occipital and mu rhythm in the motor cortex are correlated with the decline in cognitive and motor functions, respectively. Increasing alpha activity using tACS might therefore improve cognitive and motor function in the elderly. The present study explored the influence of tACS on cortical excitability in young and old healthy adults. We applied tACS at individual alpha peak frequency for 10 min (1.5 mA) to the left motor cortex. Transcranial magnetic stimulation was used to assess the changes in cortical excitability as measured by motor-evoked potentials at rest, before and after stimulation. TACS increased cortical excitability in both groups. However, our results also suggest that the mechanism behind the effects was different, as we observed an increase and decrease in intracortical inhibition in the old group and young group, respectively. Our results indicate that both groups profited similarly from the stimulation. There was no indication that tACS was more effective in conditions of low alpha power, that is, in the elderly.

Decrease of motor cortex excitability following exposure to a 20 Hz magnetic field as generated by a rotating permanent magnet.

OBJECTIVES: Rotation of a static magnet over the motor cortex (MC) generates a transcranial alternating magnetic field (tAMF), and a linked alternating electrical field. The aim of this transcranial magnetic stimulation (TMS) study is to investigate whether such fields are able to influence MC excitability, and whether there are parallels to tACS induced effects. METHODS: Fourteen healthy volunteers received 20 Hz tAMF stimulation over the MC, over the vertex, and 20 Hz tACS over the MC, each with a duration of 15 min. TMS assessments were performed before and after the interventions. Changes in motor evoked potentials (MEP), short interval intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) were evaluated. RESULTS: The tACS and the tAMF stimulation over the MC affected cortical excitability in a different way. After tAMF stimulation MEP amplitudes and ICF decreased and the effect of SICI increased. After tACS MEP amplitudes increased and there were no effects on SICI and ICF. CONCLUSIONS: The recorded single and paired pulse MEPs indicate a general decrease of MC excitability following 15 min of tAMF stimulation. SIGNIFICANCE: The effects demonstrate that devices based on rotating magnets are potentially suited to become a novel brain stimulation tool in clinical neurophysiology.

Mechanisms of Nicotinic Modulation of Glutamatergic Neuroplasticity in Humans.

The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.

Efficacy of Anodal Transcranial Direct Current Stimulation is Related to Sensitivity to Transcranial Magnetic Stimulation.

BACKGROUND: Transcranial direct current stimulation (tDCS) has become an important non-invasive brain stimulation tool for basic human brain physiology and cognitive neuroscience, with potential applications in cognitive and motor rehabilitation. To date, tDCS studies have employed a fixed stimulation level, without considering the impact of individual anatomy and physiology on the efficacy of the stimulation. This approach contrasts with the standard procedure for transcranial magnetic stimulation (TMS) where stimulation levels are usually tailored on an individual basis. OBJECTIVE/HYPOTHESIS: The present study tests whether the efficacy of tDCS-induced changes in corticospinal excitability varies as a function of individual differences in sensitivity to TMS. METHODS: We performed an archival review to examine the relationship between the TMS intensity required to induce 1 mV motor-evoked potentials (MEPs) and the efficacy of (fixed-intensity) tDCS over the primary motor cortex (M1). For the latter, we examined tDCS-induced changes in corticospinal excitability, operationalized by comparing MEPs before and after anodal or cathodal tDCS. For comparison, we performed a similar analysis on data sets in which MEPs had been obtained before and after paired associative stimulation (PAS), a non-invasive brain stimulation technique in which the stimulation intensity is adjusted on an individual basis. RESULTS: MEPs were enhanced following anodal tDCS. This effect was larger in participants more sensitive to TMS as compared to those less sensitive to TMS, with sensitivity defined as the TMS intensity required to produce MEPs amplitudes of the size of 1 mV. While MEPs were attenuated following cathodal tDCS, the magnitude of this attenuation was not related to TMS sensitivity nor was there a relationship between TMS sensitivity and responsiveness to PAS. CONCLUSION: Accounting for variation in individual sensitivity to non-invasive brain stimulation may enhance the utility of tDCS as a tool for understanding brain-behavior interactions and as a method for clinical interventions.

Dosage-dependent effect of dopamine D2 receptor activation on motor cortex plasticity in humans.

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose-response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.

Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans.

The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose-response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation.

BACKGROUND: Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h. OBJECTIVE: We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory. METHODS: The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval). RESULTS: The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity. CONCLUSION: Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.