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• Repeated spaced multi-coil TMS protocol impacts motor cortex plasticity. • Repeated spaced cortical paired associative stimulation (cPAS) caused a cumulative, dose-dependent effect on motor cortex excitability. • Repeated spaced cPAS may provide a more direct and effective method for modifying specific neural circuits. Repeated spaced sessions of repetitive transcranial magnetic stimulation (TMS) to the human primary motor cortex can lead to dose-dependent increases in motor cortical excitability. However, this has yet to be demonstrated in a defined cortical circuit. We aimed to examine the effects of repeated spaced cortical paired associative stimulation (cPAS) on excitability in the motor cortex. cPAS was delivered to the primary motor cortex (M1) and posterior parietal cortex (PPC) with two coils. In the multi-dose condition, three sessions of cPAS were delivered 50-min apart. The single-dose condition had one session of cPAS, followed by two sessions of a control cPAS protocol. Motor-evoked potentials were evaluated before and up to 40 min after each cPAS session as a measure of cortical excitability. Compared to a single dose of cPAS, motor cortical excitability significantly increased after multi-dose cPAS. Increasing the number of cPAS sessions resulted in a cumulative, dose-dependent effect on excitability in the motor cortex, with each successive cPAS session leading to notable increases in potentiation. Repeated spaced cPAS sessions summate to increase motor cortical excitability induced by single cPAS. Repeated spaced cPAS could potentially restore abilities lost due to disorders like stroke. [ABSTRACT FROM AUTHOR]

• Patients with post-COVID fatigue show reduced TMS-induced beta oscillations in SMA. • In patients, TMS-induced beta oscillatory activity in SMA negatively correlates with fatigue. • In patients, gamma- and beta- oscillatory activity is diminished in l-M1. Persistent fatigue is a major symptom of the so-called 'long-COVID syndrome', but the pathophysiological processes that cause it remain unclear. We hypothesized that fatigue after COVID-19 would be associated with altered cortical activity in premotor and motor regions. We used transcranial magnetic stimulation combined with EEG (TMS-EEG) to explore the neural oscillatory activity of the left primary motor area (l-M1) and supplementary motor area (SMA) in a group of sixteen post-COVID patients complaining of lingering fatigue as compared to a sample of age-matched healthy controls. Perceived fatigue was assessed with the Fatigue Severity Scale (FSS) and Fatigue Rating Scale (FRS). Post-COVID patients showed a remarkable reduction of beta frequency in both areas. Correlation analysis exploring linear relation between neurophysiological and clinical measures revealed a significant inverse correlation between the individual level of beta oscillations evoked by TMS of SMA with the individual scores in the FRS (r(15) = -0.596; p = 0.012). Post-COVID fatigue is associated with a reduction of TMS-evoked beta oscillatory activity in SMA. TMS-EEG could be used to identify early alterations of cortical oscillatory activity that could be related to the COVID impact in central fatigue. [ABSTRACT FROM AUTHOR]

• TMS changes resting state functional connectivity proportional to the electric field distribution of the TMS pulse. • Results offer critical insight into the mechanism underlying TMS modulation of brain connectivity. • They also show that a generalized connectivity mapping approach may inform precision targeting efforts. Transcranial magnetic stimulation (TMS) can efficiently and robustly modulate synaptic plasticity, but little is known about how TMS affects functional connectivity (rs-fMRI). Accordingly, this project characterized TMS-induced rsFC changes in depressed patients who received 3 days of left prefrontal intermittent theta burst stimulation (iTBS). rs-fMRI was collected from 16 subjects before and after iTBS. Correlation matrices were constructed from the cleaned rs-fMRI data. Electric-field models were conducted and used to predict pre-post changes in rs-fMRI. Site by orientation heatmaps were created for vectors centered on the stimulation site and a control site (contralateral motor cortex). For the stimulation site, there was a clear relationship between both site and coil orientation, and connectivity changes. As distance from the stimulation site increased, prediction accuracy decreased. Similarly, as eccentricity from the optimal orientation increased, prediction accuracy decreased. The systematic effects described above were not apparent in the heatmap centered on the control site. These results suggest that rs-fMRI following iTBS changes systematically as a function of the distribution of electrical energy delivered from the TMS pulse, as represented by the e-field model. This finding lays the groundwork for future studies to individualize TMS targeting based on how predicted rs-fMRI changes might impact psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • The stacked-coil dsTMS setup could reliably explore PMd–M1 connectivity for certain ISIs ranging from 3 to 10 ms. • Intrahemispheric PMd–M1 connectivity was inhibitory for ISIs of 3 and 5 ms, and facilitatory for 10 ms. • Replication of SICI and ICF paradigms with the stacked-coil setup achieved test–retest reliability comparable to the literature. Investigating the optimal interstimulus interval (ISI) and the 24-hour test–retest reliability for intrahemispheric dorsal premotor cortex (PMd) – primary motor cortex (M1) connectivity using dual-site transcranial magnetic stimulation (dsTMS). In 21 right-handed adults, left intrahemispheric PMd–M1 connectivity has been investigated with a stacked-coil dsTMS setup (conditioning stimulus: 75% of resting motor threshold; test stimulus: eliciting MEPs of 1–1.5 mV) at ISIs of 3, 5–8, and 10 ms. Additionally, M1–M1 short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were investigated to assess comparability to standard paired-pulse setups. Conditioning PMd led to significant inhibition of M1 output at ISIs of 3 and 5 ms, whereas 10 ms resulted in facilitation (all, p < 0.001), with a fair test–retest reliability for 3 (ICC: 0.47) and 6 ms (ICC: 0.44) ISIs. Replication of SICI (p < 0.001) and ICF (p = 0.017) was successful, with excellent test–retest reliability for SICI (ICC: 0.81). This dsTMS setup can probe the inhibitory and facilitatory PMd–M1 connections, as well as reliably replicate SICI and ICF paradigms. The stacked-coil dsTMS setup for investigating intrahemispheric PMd–M1 connectivity offers promising possibilities to better understand motor control. [ABSTRACT FROM AUTHOR]

• Advanced PD patients treated with STN-DBS displayed a lack of corticospinal suppression during movement preparation. • This lack of preparatory suppression was observed on the responding side, especially in the most-affected hand. • This deficit was unresponsive to STN-DBS. Parkinson's disease (PD) patients exhibit changes in mechanisms underlying movement preparation, particularly the suppression of corticospinal excitability – termed "preparatory suppression" – which is thought to facilitate movement execution in healthy individuals. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) being an attractive treatment for advanced PD, we aimed to study the potential contribution of this nucleus to PD-related changes in such corticospinal dynamics. On two consecutive days, we applied single-pulse transcranial magnetic stimulation to the primary motor cortex of 20 advanced PD patients treated with bilateral STN-DBS (ON vs. OFF), as well as 20 healthy control subjects. Motor-evoked potentials (MEPs) were elicited at rest or during movement preparation in an instructed-delay choice reaction time task including left- or right-hand responses. Preparatory suppression was assessed by expressing MEPs during movement preparation relative to rest. PD patients exhibited a deficit in preparatory suppression when it was probed on the responding hand side, particularly when this corresponded to their most-affected hand, regardless of their STN-DBS status. Advanced PD patients displayed a reduction in preparatory suppression which was not restored by STN-DBS. The current findings confirm that PD patients lack preparatory suppression, as previously reported. Yet, the fact that this deficit was not responsive to STN-DBS calls for future studies on the neural source of this regulatory mechanism during movement preparation. [ABSTRACT FROM AUTHOR]

• Comparing anodal tDCS paired with mindfulness meditation to sham tDCS in fibromyalgia. • Pain, quality of life and symptoms improve over time, independent of group with inconclusive mechanistic effects assessed by TMS. • Findings challenge paired tDCS and meditation in fibromyalgia treatment. This study investigated the efficacy of combining at-home anodal transcranial direct current stimulation (tDCS) of the left primary motor cortex (M1) with mindfulness meditation (MM) in fibromyalgia patients trained in mindfulness. Thirty-seven patients were allocated to receive ten daily sessions of MM paired with either anodal or sham tDCS over the primary motor cortex. Primary outcomes were pain intensity and quality of life. Secondary outcomes were psychological impairment, sleep quality, mood, affective pain, mindfulness level, and transcranial magnetic stimulation (TMS) measures of cortical excitability. Outcomes were analyzed pre- and post-treatment, with a one-month follow-up. We found post-tDCS improvement in all clinical outcomes, including mindfulness level, except for positive affect and stress, in both groups without significant difference between active and sham conditions. No significant group*time interaction was found for all clinical and TMS outcomes. Our findings demonstrate no synergistic or add-on efffect of anodal tDCS of the left M1 compared to the proper effect of MM in patients with fibromyalgia. Our findings challenge the potential of combining anodal tDCS of the left M1 and MM in fibromyalgia. [ABSTRACT FROM AUTHOR]

• Strength-duration time constant (SDTC) may now be determined for cortical motor neurones. • SDTC is significantly reduced in ALS patients and is correlated with ALS functional rating score, and rate of disease progression. • An increase in transient Na+ conductances may account for the reduction in SDTC. Strength-duration time constant (SDTC) may now be determined for cortical motor neurones, with activity mediated by transient Na+ conductances. The present study determined whether cortical SDTC is abnormal and linked to the pathogenesis of amyotrophic lateral sclerosis. Cortical SDTC and rheobase were estimated from 17 ALS patients using a controllable pulse parameter transcranial magnetic stimulation (cTMS) device. Resting motor thresholds (RMTs) were determined at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M−ratio of 0.1, using a figure-of-eight coil applied to the primary motor cortex. SDTC was significantly reduced in ALS patients (150.58 ± 9.98 µs; controls 205.94 ± 13.7 µs, P < 0.01). The reduced SDTC correlated with a rate of disease progression (Rho = -0.440, P < 0.05), ALS functional rating score (ALSFRS-R) score (Rho = 0.446, P < 0.05), and disease duration (R = 0.428, P < 0.05). The degree of change in SDTC was greater in patients with cognitive abnormalities as manifested by an abnormal total Edinburgh Cognitive ALS Screen score (140.5 ± 28.7 µs, P < 0.001) and ALS-specific subscore (141.7 ± 33.2 µs, P = 0.003). Cortical SDTC reduction was associated with a more aggressive ALS phenotype, or with more prominent cognitive impairment. An increase in transient Na+ conductances may account for the reduction in SDTC, linked to the pathogenesis of ALS. [ABSTRACT FROM AUTHOR]

• Neuromodulation techniques have a therapeutic potential in movement disorders. • Techniques of invasive and non-invasive brain stimulation, spinal cord stimulation, and focused ultrasound are reviewed. • Botulinum toxin injections can benefit from electromyography to accurately identify the muscles to treat. In this review, different aspects of the use of clinical neurophysiology techniques for the treatment of movement disorders are addressed. First of all, these techniques can be used to guide neuromodulation techniques or to perform therapeutic neuromodulation as such. Neuromodulation includes invasive techniques based on the surgical implantation of electrodes and a pulse generator, such as deep brain stimulation (DBS) or spinal cord stimulation (SCS) on the one hand, and non-invasive techniques aimed at modulating or even lesioning neural structures by transcranial application. Movement disorders are one of the main areas of indication for the various neuromodulation techniques. This review focuses on the following techniques: DBS, repetitive transcranial magnetic stimulation (rTMS), low-intensity transcranial electrical stimulation, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), and focused ultrasound (FUS), including high-intensity magnetic resonance-guided FUS (MRgFUS), and pulsed mode low-intensity transcranial FUS stimulation (TUS). The main clinical conditions in which neuromodulation has proven its efficacy are Parkinson's disease, dystonia, and essential tremor, mainly using DBS or MRgFUS. There is also some evidence for Tourette syndrome (DBS), Huntington's disease (DBS), cerebellar ataxia (tDCS), and axial signs (SCS) and depression (rTMS) in PD. The development of non-invasive transcranial neuromodulation techniques is limited by the short-term clinical impact of these techniques, especially rTMS, in the context of very chronic diseases. However, at-home use (tDCS) or current advances in the design of closed-loop stimulation (tACS) may open new perspectives for the application of these techniques in patients, favored by their easier use and lower rate of adverse effects compared to invasive or lesioning methods. Finally, this review summarizes the evidence for keeping the use of electromyography to optimize the identification of muscles to be treated with botulinum toxin injection, which is indicated and widely performed for the treatment of various movement disorders. [ABSTRACT FROM AUTHOR]

• Early local TMS-evoked potentials (EL-TEPs) varied significantly across the dlPFC as a function of TMS target. • TMS targets with less muscle artifact had significantly larger EL-TEPs. • Selection of a postero-medial target increased EL-TEPs by 102% compared to anterior targets. Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an effective treatment for depression, but the neural effects after TMS remains unclear. TMS paired with electroencephalography (TMS-EEG) can causally probe these neural effects. Nonetheless, variability in single pulse TMS-evoked potentials (TEPs) across dlPFC subregions, and potential artifact induced by muscle activation, necessitate detailed mapping for accurate treatment monitoring. To characterize early TEPs anatomically and temporally (20–50 ms) close to the TMS pulse (EL-TEPs), as well as associated muscle artifacts (<20 ms), across the dlPFC. We hypothesized that TMS location and angle influence EL-TEPs, and specifically that conditions with larger muscle artifact may exhibit lower observed EL-TEPs due to over-rejection during preprocessing. Additionally, we sought to determine an optimal group-level TMS target and angle, while investigating the potential benefits of a personalized approach. In 16 healthy participants, we applied single-pulse TMS to six targets within the dlPFC at two coil angles and measured EEG responses. Stimulation location significantly influenced observed EL-TEPs, with posterior and medial targets yielding larger EL-TEPs. Regions with high EL-TEP amplitude had less muscle artifact, and vice versa. The best group-level target yielded 102% larger EL-TEP responses compared to other dlPFC targets. Optimal dlPFC target differed across subjects, suggesting that a personalized targeting approach might boost the EL-TEP by an additional 36%. EL-TEPs can be probed without significant muscle-related confounds in posterior-medial regions of the dlPFC. The identification of an optimal group-level target and the potential for further refinement through personalized targeting hold significant implications for optimizing depression treatment protocols. [ABSTRACT FROM AUTHOR]

• Transcranial magnetic stimulation is an objective biomarker of upper motor neuron dysfunction in motor neuron disease (MND). • Cortical hyperexcitability is mediated by cortical disinhibition and increased facilitation. • Neuroimaging biomarkers of upper motor neuron dysfunction in MND exhibit utility. Identifying upper motor neuron (UMN) dysfunction is fundamental to the diagnosis and understanding of disease pathogenesis in motor neuron disease (MND). The clinical assessment of UMN dysfunction may be difficult, particularly in the setting of severe muscle weakness. From a physiological perspective, transcranial magnetic stimulation (TMS) techniques provide objective biomarkers of UMN dysfunction in MND and may also be useful to interrogate cortical and network function. Single, paired- and triple pulse TMS techniques have yielded novel diagnostic and prognostic biomarkers in MND, and have provided important pathogenic insights, particularly pertaining to site of disease onset. Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) and increased short interval intracortical facilitation, has been associated with the onset of lower motor neuron degeneration, along with patterns of disease spread, development of specific clinical features such as the split hand phenomenon, and may provide an indication about the rate of disease progression. Additionally, reduction of SICI has emerged as a potential diagnostic aid in MND. The triple stimulation technique (TST) was shown to enhance the diagnostic utility of conventional TMS measures in detecting UMN dysfunction in MND. Separately, sophisticated brain imaging techniques have uncovered novel biomarkers of neurodegeneration that have bene associated with progression. The present review will discuss the utility of TMS and brain neuroimaging derived biomarkers of UMN dysfunction in MND, focusing on recently developed TMS techniques and advanced neuroimaging modalities that interrogate structural and functional integrity of the corticomotoneuronal system, with an emphasis on pathogenic, diagnostic, and prognostic utility. [ABSTRACT FROM AUTHOR]

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment. [ABSTRACT FROM AUTHOR]

• This study examined the effects of intermittent (iTBS), continuous (cTBS) or sham TBS (sTBS) of the left DLPFC before a stressor. • cTBS compared to sTBS and iTBS resulted in an attenuated stress-induced cortisol response in high compared to low trait ruminators. • There were rumination independent TBS effects on mood and heart rate, but not on other psychophysiological measures of stress. Previous studies suggest that theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC) might be a promising approach to modulate stress-reactive rumination and the associated psychophysiological stress response. Crucially, individuals showing higher levels of trait rumination might benefit more from prefrontal stimulation. In this sham-controlled study, 127 healthy individuals, with varying ruminative tendencies, received a single-session of intermittent TBS (iTBS), continuous TBS (cTBS) or sham TBS (sTBS) over the left DLPFC before being confronted with a Trier Social Stress Test. Results showed significant TBS effects on salivary cortisol as a function of trait rumination. cTBS, as compared to sTBS and iTBS, resulted in an attenuated stress-induced cortisol response in high compared to low trait ruminators. Although independent of trait rumination levels, cTBS showed positive effects on stress-related changes in mood and, both cTBS and iTBS (versus sham) presented an enhanced heart rate recovery following the stressor. We found no evidence for (trait rumination-dependent) TBS effects on stress-reactive rumination, negative affect, subjective stress or heart rate variability. cTBS shows beneficial effects on certain measures of stress, especially in high trait ruminators. These findings highlight the importance of accounting for individual differences when examining TBS effects. [ABSTRACT FROM AUTHOR]

• A detailed neurophysiological and biomechanical characterization of age-related oropharyngeal dysphagia is reported. • To our knowledge, this is the first time that an impairment of the pharyngeal motor cortical pathway with age has been described. • Pharyngeal sensory/afferent impairment may be the critical pathophysiological element for oropharyngeal dysphagia in older patients. To characterize swallowing biomechanics and neurophysiology in older patients with oropharyngeal dysphagia (OD). Observational study in 12 young healthy volunteers (HV), 9 older HV (OHV) and 12 older patients with OD with no previous diseases causing OD (OOD). Swallowing biomechanics were measured by videofluoroscopy, neurophysiology with pharyngeal sensory (pSEP) and motor evoked-potentials (pMEP) to intrapharyngeal electrical and transcranial magnetic stimulation (TMS), respectively, and salivary neuropeptides with enzyme-linked immunosorbent assay (ELISA). 83.3% of OOD patients had unsafe swallows (Penetration-Aspiration scale = 4.3 ± 2.1; p < 0.0001) with delayed time to laryngeal vestibule closure (362.5 ± 73.3 ms; p < 0.0001) compared to both HV groups. OOD patients had: (a) higher pharyngeal sensory threshold (p = 0.009) and delayed pSEP P1 and N2 latencies (p < 0.05 vs HV) to electrical stimulus; and (b) higher pharyngeal motor thresholds to TMS in both hemispheres (p < 0.05) and delayed pMEPs latencies (right, p < 0.0001 HV vs OHV/OOD; left, p < 0.0001 HV vs OHV/OOD). OOD patients have unsafe swallow and delayed swallowing biomechanics, pharyngeal hypoesthesia with disrupted conduction of pharyngeal sensory inputs, and reduced excitability and delayed cortical motor response. These findings suggest new elements in the pathophysiology of aging-associated OD and herald new and more specific neurorehabilitation treatments for these patients. [ABSTRACT FROM AUTHOR]

• Thirty-nine studies explored the effect of age on responsiveness to non-invasive brain stimulation neuroplasticity paradigms. • Pooled findings revealed age-dependent reduction in corticospinal excitability following certain neuroplasticity paradigms. • Considerable heterogeneity within some paradigms was evident, limiting interpretations of pooled analyses. We aimed to summarise and critically appraise the available evidence for the effect of age on responsiveness to non-invasive brain stimulation (NBS) paradigms delivered to the primary motor cortex. Four databases (Medline, Embase, PsycINFO and Scopus) were searched from inception to February 7, 2023. Studies investigating age group comparisons and associations between age and neuroplasticity induction from NBS paradigms were included. Only studies delivering neuroplasticity paradigms to the primary motor cortex and responses measured via motor-evoked potentials (MEPs) in healthy adults were considered. 39 studies, encompassing 40 experiments and eight NBS paradigms were included: paired associative stimulation (PAS; n = 12), repetitive transcranial magnetic stimulation (rTMS; n = 2), intermittent theta burst stimulation (iTBS; n = 8), continuous theta burst stimulation (cTBS; n = 7), transcranial direct and alternating current stimulation ((tDCS; n = 7; tACS; n = 2)), quadripulse stimulation (QPS; n = 1) and i-wave periodic transcranial magnetic stimulation (iTMS; n = 1). Pooled findings from PAS paradigms suggested older adults have reduced post-paradigm responses, although there was considerable heterogeneity. Mixed results were observed across all other NBS paradigms and post-paradigm timepoints. Whilst age-dependent reduction in corticospinal excitability is possible, there is extensive inter- and intra-individual variability both within and between studies, making it difficult to draw meaningful conclusions from pooled analyses. [ABSTRACT FROM AUTHOR]

• This study investigated the cortical silent period (CSP) characteristics in stronger biceps (power = 3–5) and weaker triceps (power = 1–3) after SCI. • The CSP from the biceps had a longer duration, whereas it was delayed and shallow for the triceps in individuals with SCI. • The CSP characteristics were associated with upper arm functional ability supporting their relevance for motor recovery after SCI. Corticospinal inhibitory mechanisms are relevant to functional recovery but remain poorly understood after spinal cord injury (SCI). Post-injury characteristics of contralateral silent period (CSP), a measure of corticospinal inhibition evaluated using transcranial magnetic stimulation (TMS), is inconsistent in literature. We envisioned that investigating CSP across muscles with varying degrees of weakness may be a reasonable approach to resolve inconsistencies and elucidate the relevance of corticospinal inhibition for upper extremity function following SCI. We studied 27 adults with chronic C1-C8 SCI (age 48.8 ± 16.1 years, 3 females) and 16 able-bodied participants (age 33.2 ± 11.8 years, 9 females). CSP characteristics were assessed across biceps (muscle power = 3–5) and triceps (muscle power = 1–3) representing stronger and weaker muscles, respectively. We assessed functional abilities using the Capabilities of the Upper Extremity Test (CUE-T). Participants with chronic SCI had prolonged CSPs for biceps but delayed and diminished CSPs for triceps compared to able-bodied participants. Early-onset CSPs for biceps and longer, deeper CSPs for triceps correlated with better CUE-T scores. Corticospinal inhibition is pronounced for stronger biceps but diminished for weaker triceps muscle in SCI indicating innervation relative to the level of injury matters in the study of CSP. Nevertheless, corticospinal inhibition or CSP holds relevance for upper extremity function following SCI. [ABSTRACT FROM AUTHOR]

• Ear-brain pathway responsible for speech perception is altered in hearing loss. • rTMS protocol directed to the auditory association cortex might restore its functionality. • Improvements of speech perception are observed after 5 days of rTMS in deaf patients. Sensorineural hearing-loss (SHL) is accompanied by changes in the entire ear-brain pathway and its connected regions. While hearing-aid (HA) partially compensates for SHL, speech perception abilities often continue to remain poor, resulting in consequences in everyday activities. Repetitive transcranial magnetic stimulation (rTMS) promotes cortical network plasticity and may enhance language comprehension in SHL patients. 27 patients using HA and with SHL were randomly assigned to a treatment protocol consisting of five consecutive days of either real (Active group: 13 patients) or placebo rTMS (Sham group: 14 patients). The stimulation parameters were as follows: 2-second trains at 10 Hz, 4-second inter-train-interval, and 1800 pulses. Neuronavigated rTMS was applied over the left superior temporal sulcus. Audiological tests were administered before (T0), immediately after (T1), and one week following treatment completion (T2) to evaluate the speech reception threshold (SRT) and the Pure Tone Average (PTA). In the context of a general improvement likely due to learning, the treatment with real rTMS induced significant reduction of the SRT and PTA at T1 and T2 versus placebo. The long-lasting effects on SRT and PTA observed in the Active group indicates that rTMS administered over the auditory cortex could promote sustained neuromodulatory-induced changes in the brain, improving the perception of complex sentences and pure tones reception skills. Five days of rTMS treatment enhances overall speech intelligibility and PTA in SHL patients. [ABSTRACT FROM AUTHOR]

• We developed a novel dual-site TMS setup to stimulate two adjacent brain regions. • It is subject to fewer technical and spatial limitations than previous attempts. • This enables more accurate and repeatable targeting of brain regions. Using dual-site transcranial magnetic stimulation (dsTMS), the effective connectivity between the primary motor cortex (M1) and adjacent brain areas such as the dorsal premotor cortex (PMd) can be investigated. However, stimulating two brain regions in close proximity (e.g., ±2.3 cm for intrahemispheric PMd–M1) is subject to considerable spatial restrictions that potentially can be overcome by combining two standard figure-of-eight coils in a novel dsTMS setup. After a technical evaluation of its induced electric fields, the dsTMS setup was tested in vivo (n = 23) by applying a short-interval intracortical inhibition (SICI) protocol. Additionally, the intrahemispheric PMd–M1 interaction was probed. E-field modelling was performed using SimNIBS. The technical evaluation yielded no major alterations of the induced electric fields due to coil overlap. In vivo , the setup reliably elicited SICI. Investigating intrahemispheric PMd–M1 interactions was feasible (inter-stimulus interval 6 ms), resulting in modulation of M1 output. The presented dsTMS setup provides a novel way to stimulate two adjacent brain regions with fewer technical and spatial limitations than previous attempts. This dsTMS setup enables more accurate and repeatable targeting of brain regions in close proximity and can facilitate innovation in the field of effective connectivity. [ABSTRACT FROM AUTHOR]

• Non-invasive brain and spinal stimulation techniques have been investigated as a potential treatment in motoneuron disease. • Stimulation methods aim at counteracting glutamate-mediated excitotoxicity leading to motoneuron degeneration. • Targeted, individualized and home-deliverable treatments are critical challenges for future advancements. Non-invasive brain stimulation techniques have been exploited in motor neuron disease (MND) with multifold objectives: to support the diagnosis, to get insights in the pathophysiology of these disorders and, more recently, to slow down disease progression. In this review, we consider how neuromodulation can now be employed to treat MND, with specific attention to amyotrophic lateral sclerosis (ALS), the most common form with upper motoneuron (UMN) involvement, taking into account electrophysiological abnormalities revealed by human and animal studies that can be targeted by neuromodulation techniques. This review article encompasses repetitive transcranial magnetic stimulation methods (including low-frequency, high-frequency, and pattern stimulation paradigms), transcranial direct current stimulation as well as experimental findings with the newer approach of trans-spinal direct current stimulation. We also survey and discuss the trials that have been performed, and future perspectives. [ABSTRACT FROM AUTHOR]

• The degree of LTP-like plasticity was correlated with amyloid and tau biomarkers. • The degree of LTP-like plasticity was correlated with cognitive function. • NBS techniques using QPS5 can be used as a neurophysiological biomarker for cognitive decline related to AD pathology. Amyloid-beta (Aβ) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer's disease (AD) diagnosis in subjects with cognitive decline. Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aβ42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with 11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aβ42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology. [ABSTRACT FROM AUTHOR]

• Quantifying mirror activity in ALS patients can be readily achieved using a novel algorithm. • Increase of mirror activity seems to precede changes in other measures of motor function and transcallosal inhibition. • Further studies are warranted to evaluate the potential utility of this approach as a biomarker for ALS. To investigate mirror activity in amyotrophic lateral sclerosis (ALS) patients, using a simple paradigm of signal quantification. Patients were asked to perform a brief isometric maximum contraction of the abductor digiti minimi (ADM) or tibialis anterior (TA) on one side, while relaxing the contralateral side of the body. Both sides were investigated. Signals were stored and analyzed offline, for quantification of electromyographic signal. Clinical signs of upper motor neuron (UMN) dysfunction, transcranial magnetic stimulation (TMS) for the upper (UL) and lower limbs (LL), the ADM ipsilateral cortical silent period (iSP) and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) cognitive scale were also investigated. 42 ALS patients were included. In the 4 investigated muscles the amount of mirror activity was significantly higher than in the matched healthy group. The amount of mirror activity was similar between sides, but significantly higher in UL and LL with abnormal TMS results for ADM (p = 0.005) and TA (p = 0.002), as well as in UL with abnormal iSP values (p = 0.009). No association was found between mirror activity and clinical signs of UMN involvement. Mirror activity is a common phenomenon in ALS. Mirror activity intensity corresponds to the severity of UMN dysfunction, as measured by TMS, and probably derives from the abnormal transcallosal inhibition as mirrored by iSP abnormality. Mirror activity is increased in ALS and is associated with abnormal transcallosal inhibition and UMN dysfunction. [ABSTRACT FROM AUTHOR]

• High-frequency rTMS targeting the left DLPFC had significant therapeutic efficacy for patients with post-stroke depression (PSD). • RTMS treatment for PSD patients in subacute phase (1–6 months) had significant antidepressant effect. • The Hamilton Depression Rating Scale is sensitive to evaluate the treatment-induced depressive alleviations in PSD patients. This meta-analysis investigated the therapeutic efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) for treatment of post-stroke depression (PSD). Ten articles with 266 patients in rTMS group and 258 patients in control group were included. The primary outcome was performed to examine the efficacy of rTMS for PSD. Secondary outcomes of response rates and remission rates and subgroup analyses were further explored. Our meta-analysis revealed a significant pooled effect size (the standard mean difference (SMD) was −1.45 points (95% CI, −2.04 to −0.86; p < 0.00001)). The odds ratio (OR) of the response rate and remission rate were 8.41 (95% CI, 2.52–28.12, p = 0.0005) and 6.04 (95% CI, 1.5–24.39, p = 0.01). Moreover, rTMS treatment for PSD patients in subacute phase and targeting the left DLPFC at 5-cm anterior to the left motor hotspot or the midpoint of the middle frontal gyrus showed significant antidepressant effect. In addition, the Hamilton Depression Rating Scale (HAMD) was sensitive to detect depressive changes in patients. Our meta-analysis elucidated that the application of high-frequency rTMS over the left DLPFC was an effective treatment alternative for PSD. Our meta-analysis may help to develop more reasonable treatment strategies in clinical practice for PSD patients. [ABSTRACT FROM AUTHOR]

• Patients with Lewy Body Diseases and visual hallucinations have reduced effective connectivity of the right intraparietal sulcus. • Visual hallucinations likely reflect defective top-down attentional control over bottom-up visual processing. • Transcranial magnetic stimulation coupled with electroencephalography detects network changes underlying visual hallucinations. To assess the changes in effective connectivity of important regions of the visual network (VIS) and dorsal attention network (DAN) underlying visual hallucinations (VHs) in Dementia with Lewy Bodies (DLB), Parkinson's Disease (PD) and Parkinson's Disease Dementia (PDD), as measured by a transcranial magnetic stimulation-electroencephalographic technique (TMS-EEG). We stimulated the right visual cortex (V1/V2), the right intraparietal sulcus and the right frontal eye fields, two key regions of the DAN, and measured TMS-evoked cortical activation within the VIS and the DAN. We compared 11 patients with VHs and 15 patients without VHs. Patients with VHs showed lower TMS-evoked cortical activation within the DAN following intraparietal sulcus and frontal eye fields stimulation than patients without VHs. No difference was found between patients with and without cognitive impairment. Also, when considering only patients with cognitive impairment, VHs were associated with lower TMS-evoked cortical activation following intraparietal sulcus stimulation. DLB, PD, and PDD patients with VHs had less effective connectivity of the right intraparietal sulcus within the DAN than patients without VHs. We provided the first evidence that VHs are associated with specific intraparietal sulcus dysfunction within the DAN in patients with PDD, PD, and DLB. [ABSTRACT FROM AUTHOR]

• Laser-paired associative stimulation elicits abnormal primary motor cortex (M1) plasticity in patients with chronic pain. • In chronic pain, impaired M1 plasticity reflects abnormal pain-motor integration. • Abnormal pain-motor integration plays a prominent role in the pathophysiology of chronic pain. Chronic pain may lead to functional changes in several brain regions, including the primary motor cortex (M1). Our neurophysiological study aimed to probe M1 plasticity, through a non-invasive transcranial magnetic stimulation protocol, in a cohort of patients with chronic pain. Twenty patients with chronic pain (age ± SD: 62.9 ± 9.9) and 20 age- and sex-matched healthy controls (age ± SD: 59.6 ± 15.8) were recruited. Standardized scales were used for the evaluation of pain severity. Neurophysiological measures included laser-evoked potentials (LEPs) and motor-evoked potentials (MEPs) collected at baseline and over 60 minutes following a standardized Laser-paired associative stimulation (Laser-PAS) protocol. LEPs and MEPs were comparable in patients with chronic pain and controls. The pain threshold was lower in patients than in controls. Laser-PAS elicited decreased responses in patients with chronic pain. The response to Laser-PAS was similar in subgroups of patients with different chronic pain phenotypes. M1 plasticity, as tested by Laser-PAS, is altered in patients with chronic pain, possibly reflecting abnormal pain-motor integration processes. Chronic pain is associated with a disorder of M1 plasticity raising from abnormal pain-motor integration. [ABSTRACT FROM AUTHOR]

• Cortico-cortical paired associative stimulation (ccPAS) is a modulation protocol based on Hebbian plasticity. • ccPAS offers spatiotemporal specificity to modulate brain networks. • ccPAS effects have been assessed using EMG, behavioral outcomes, EEG, and fMRI. Cortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at specific interstimulus intervals (ISI) delivered to distant cortical areas. The goal of this article is to systematically review its efficacy in inducing plasticity in humans focusing on stimulation parameters and hypotheses of underlying neurophysiology. A systematic review of the literature from 2009–2023 was undertaken to identify all articles utilizing ccPAS to study brain plasticity and connectivity. Six electronic databases were searched and included. 32 studies were identified. The studies targeted connections within the same hemisphere or between hemispheres. 28 ccPAS studies were in healthy participants, 1 study in schizophrenia, and 1 in Alzheimer's disease (AD) patients. 2 additional studies used cortico-cortical repetitive paired associative stimulation (cc-rPAS) in generalized anxiety disorder (GAD) patients. Outcome measures include electromyography (EMG), behavioral measures, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). ccPAS seems to be able to modulate brain connectivity depending on the ISI. ccPAS can be used to modulate corticospinal excitability, brain activity, and behavior. Although the stimulation parameters used across studies reviewed in this paper are varied, ccPAS is a promising approach for basic research and potential clinical applications. Recent advances in neuroscience have caused a shift of interest from the study of single areas to a more complex approach focusing on networks of areas that orchestrate brain activity. Consequently, the TMS community is also witnessing a change, with a growing interest in targeting multiple brain areas rather than a single locus, as evidenced by an increasing number of papers using ccPAS. In light of this new enthusiasm for brain connectivity, this review summarizes existing literature and stimulation parameters that have proven effective in changing electrophysiological, behavioral, or neuroimaging-derived measures. [ABSTRACT FROM AUTHOR]

• TMS measures of cortical excitability modulation are variable and unstable across time. • Significant facilitation was found only on the brain hemisphere where iTBS was applied. • Cortical-excitability modulation was stable and no associations were found between psychological factors and modulation. Transcranial Magnetic Stimulation (TMS) allows for cortical-excitability (CE) assessment and its modulation has been associated with neuroplasticity-like phenomena, thought to be impaired in neuropsychiatric disorders. However, the stability of these measures has been challenged, defying their potential as biomarkers. This study aimed to test the temporal stability of cortical-excitability modulation and study the impact of individual and methodological factors in determining within- and between-subject variability. We recruited healthy-subjects to assess motor cortex (MC) excitability modulation, collecting motor evoked potentials (MEP) from both hemispheres, before and after left-sided intermittent theta burst stimulation (iTBS), to obtain a measure of MEPs change (delta-MEPs). To assess stability across-time, the protocol was repeated after 6 weeks. Socio-demographic and psychological variables were collected to test association with delta-MEPs. We found modulatory effects on left MC and not on right hemisphere following iTBS of left MC. Left delta-MEP was stable across-time when performed immediately after iTBS (ICC = 0.69), only when obtained first in left hemisphere. We discovered similar results in a replication cohort testing only left MC (ICC = 0.68). No meaningful associations were found between demographic and psychological factors and delta-MEPs. Delta-MEP is stable immediately after modulation and not impacted by different individual factors, including expectation about TMS-effect. Motor cortex excitability modulation immediately after iTBS should be further explored as a potential biomarker for neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

• Clinical manifestations of the long COVID syndrome include cognitive impairments, named "brain fog". • Previous literature suggest possible mechanisms that might result in altered cortical excitability. • This study confirms impaired glutamate and GABAb regulatory pathways in long COVID "brain fog". Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single "paired-pulse" transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI). We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex. MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients' performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001). Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found. These findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with "brain fog". [ABSTRACT FROM AUTHOR]

[Display omitted] • The excitability and sensorimotor integration of face and hand primary motor cortex in oromandibular dystonia (OMD) was studied. • In OMD, sensorimotor integration and cortical excitability were altered specifically in face primary motor cortex. • In OMD, the integration between sensory inflow and motor output is disrupted at cortical level with topographic specificity. To comprehensively investigate excitability in face and hand M1 and sensorimotor integration in oromandibular dystonia (OMD) patients. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short (SAI) and long (LAI) afferent inhibition were investigated in face and hand M1 using transcranial magnetic stimulation protocols in 10 OMD patients. Data were compared with those obtained in 10 patients with focal hand dystonia (FHD), in 10 patients with blepharospasm (BSP), and 10 matched healthy subjects (HS). Results demonstrated that in OMD patients SICI was reduced in face M1 (p < 0.001), but not in hand M1, compared to HS. In FHD, SICI was significantly impaired in hand M1 (p = 0.029), but not in face M1. In BSP, SICI was normal in both face and hand M1 while ICF and LAI were normal in all patient groups and cortical area tested. SAI was significantly reduced (p = 0.003) only in the face M1 of OMD patients. In OMD, SICI and SAI were significantly reduced. These abnormalities are specific to the motor cortical area innervating the muscular district involved in focal dystonia. In OMD, the integration between sensory inflow and motor output seem to be disrupted at cortical level with topographic specificity. [ABSTRACT FROM AUTHOR]

• The TMS pulse shape and selection of pulse widths influences the properties of the cortical strength-duration curve. • Larger hyperpolarizing TMS pulse trailing phase increases motor thresholds resulting in longer cortical strength-duration time constant and smaller rheobase. • Modulation of transient sodium channels by the trailing hyperpolarising phase is likely to mediate the effects of TMS pulse shape on cortical strength-duration curve properties. The aim of present study was to explore the effects of different combinations of transcranial magnetic stimulation (TMS) pulse width and pulse shape on cortical strength-duration time constant (SDTC) and rheobase measurements. Resting motor thresholds (RMT) at pulse widths (PW) of 30, 45, 60, 90 and 120 µs and M−ratios of 0.2, 0.1 and 0.025 were determined using figure-of-eight coil with initial posterior-to-anterior induced current. The M−ratio indicates the relative phases of the induced current with lower values signifying a more unidirectional stimulus. Strength-duration time constant (SDTC) and rheobase were estimated for each M−ratio and various PW combinations. Simulations of biophysically realistic cortical neuron models assessed underlying neuronal populations and physiological mechanisms mediating pulse shape effects on strength-duration properties. The M−ratio exerted significant effect on SDTC (F (2,44) = 4.386, P = 0.021), which was longer for M−ratio of 0.2 (243.4 ± 61.2 µs) compared to 0.025 (186.7 ± 52.5 µs, P = 0.034). Rheobase was significantly smaller when assessed with M−ratio 0.2 compared to 0.025 (P = 0.026). SDTC and rheobase values were most consistent with pulse width sets of 30/45/60/90/120 µs, 30/60/90/120 µs, and 30/60/120 µs. Simulation studies indicated that isolated pyramidal neurons in layers 2/3, 5, and large basket-cells in layer 4 exhibited SDTCs comparable to experimental results. Further, simulation studies indicated that reducing transient Na+ channel conductance increased SDTC with larger increases for higher M−ratios. Cortical strength-duration curve properties vary with pulse shape, and the modulating effect of the hyperpolarising pulse phase on cortical axonal transient Na+ conductances could account for these changes, although a shift in the recruited neuronal populations may contribute as well. The dependence of the cortical strength-duration curve properties on the TMS pulse shape and pulse width selection underscores the need for consistent measurement methods across studies and the potential to extract information about pathophysiological processes. [ABSTRACT FROM AUTHOR]

• Clinical diagnostic utility of transcranial magnetic stimulation (TMS) has been established in neurological disorders. • Paired-pulse TMS exhibits utility in neurodegenerative, movement, episodic, and functional disorders. • TMS-EEG provides novel parameter (cortical excitability, effective connectivity, response complexity) for neurological diseases. The review provides a comprehensive update ( previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504 – 32 ) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity. [ABSTRACT FROM AUTHOR]

• We evaluated the efficacy of intermittent theta-burst stimulation (iTBS) in postoperative care across two cortical targets. • iTBS reduced anaesthetic pump attempts. • This effect was unique to DLPFC stimulation while M1 had no effect. Repetitive transcranial magnetic stimulation (rTMS) may be a relevant method to assist postoperative pain. However, studies to date have only used conventional 10 Hz rTMS and targeted the DLPFC for postoperative pain. A more recent form of rTMS, termed intermittent Theta Burst Stimulation (iTBS), enables to increase cortical excitability in a short period of time. This preliminary double-blind, randomised, sham controlled study was designed to evaluate the efficacy of iTBS in postoperative care across two distinct stimulation targets. A group of 45 patients post laparoscopic surgery were randomised to receive a single session of iTBS over either the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), or Sham stimulation (1:1:1 ratio). Outcome measurements were number of pump attempts, total anaesthetic volume used, and self-rated pain experience, assessed at 1 hour, 6 hours, 24 hours, and 48 hours post stimulation. All randomised patients were analysed (n = 15 in each group). Compared to Sham stimulation, DLPFC-iTBS reduced pump attempts at 6 (DLPFC = 0.73 ± 0.88, Sham = 2.36 ± 1.65, P = 0.031), 24 (DLPFC = 1.40 ± 1.24, Sham = 5.03 ± 3.87, P = 0.008), and 48 (DLPFC = 1.47 ± 1.41, Sham = 5.87 ± 4.34, P = 0.014) hours post-surgery, whereby M1 stimulation had no effect. No group effect was observed on total anaesthetics, which was mainly provided through the continuous administration of opioids at a set speed for each group. There was also no group or interaction effect on pain ratings. Pump attempts were positively associated with pain ratings in the DLPFC (r = 0.59, P = 0.02) and M1 (r = 0.56, P = 0.03) stimulation. Our findings show that iTBS to the DLPFC reduces pump attempts for additional anaesthetics following a laparoscopic surgery. However, reduced pump attempts by DLPFC stimulation did not translate into a significantly smaller volume of total anaesthetic, due to the continuous administration of opioids at a set speed for each group. Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management. [ABSTRACT FROM AUTHOR]

• Stroke survivors demonstrate reduced interhemispheric inhibition (IHI) at rest and reduced IHI modulation with muscle contraction compared to neurotypical older adults. • Stroke survivors with greater reduction of IHI with contraction had greater motor impairment and mirroring. • Findings support the importance of characterizing state-dependent neural circuitry to understand post-stroke motor behavior. To investigate state-dependent interhemispheric inhibition (IHI) in chronic stroke survivors compared to neurotypical older adult controls, and test whether abnormal IHI modulation was associated with upper extremity motor behavior. Dual-coil transcranial magnetic stimulation (TMS) measured IHI bi-directionally, between non-lesioned and lesioned motor cortex (M1) in two activity states: (1) at rest and (2) during contralateral isometric hand muscle contraction. IHI was tested by delivering a conditioning stimulus 8-msec or 50-msec prior to a test stimulus over contralateral M1. Paretic motor behavior was assessed by clinical measures of impairment, strength, and dexterity, and mirroring activity in the non-paretic hand. Stroke survivors demonstrated reduced IHI at rest, and less IHI modulation (active – rest) compared to controls. Individual differences in IHI modulation were related to motor behavior differences where greater IHI modulation was associated with greater motor impairment and more mirroring. In contrast, there were no relationships between IHI at rest and motor behavior. Abnormal state-dependent interhemispheric circuit activity may be more sensitive to post-stroke motor deficits than when assessed in a single motor state. Characterizing state-dependent changes in neural circuitry may enhance models of stroke recovery and inform rehabilitation interventions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Low natural frequency and amplitude of TMS-EEG responses indicate high risk of post-stroke delirium (PSD). • Low TMS-evoked connectivity indicate high risk of PSD. • Low perturbation complexity index (PCIST) indicate high risk of PSD. Post-stroke delirium (PSD) is a frequent and with regard to outcome unfavorable complication in acute stroke. The neurobiological mechanisms predisposing to PSD remain poorly understood, and biomarkers predicting its risk have not been established. We tested the hypothesis that hypoexcitable or disconnected brain networks predispose to PSD by measuring brain reactivity to transcranial magnetic stimulation with electroencephalography (TMS-EEG). We conducted a cross-sectional study in 33 acute stroke patients within 48 hours of stroke onset. Brain reactivity to single-pulse TMS of dorsolateral prefrontal cortex, primary motor cortex and superior parietal lobule of the right hemisphere was quantified by response intensity, effective connectivity, perturbational complexity index (PCIST), and natural frequency of the TMS-EEG response. PSD development was clinically tracked every 8 hours before and for 7 days following TMS-EEG. Fourteen patients developed PSD while 19 patients did not. The PSD group showed lower excitability, effective connectivity, PCIST and natural frequency compared to the non-PSD group. The maximum PCIST over all three TMS sites demonstrated largest classification accuracy with a ROC-AUC of 0.943. This effect was independent of lesion size, affected hemisphere and stroke severity. Maximum PCIST and maximum natural frequency correlated inversely with delirium duration. Brain reactivity to TMS-EEG can unravel brain network states of reduced excitability, effective connectivity, perturbational complexity and natural frequency that identify acute stroke patients at high risk for development of delirium. Findings provide novel insight into the pathophysiology of pre-delirium brain states and may promote effective delirium prevention strategies in those patients at high risk. [ABSTRACT FROM AUTHOR]

[Display omitted] • Combined tendon reflex and MEP recordings improve ALS diagnosis. • Corticospinal conduction time to lower limbs increases in ALS. • Electrophysiological hyperreflexia is helpful to assess clinical hyperreflexia. This retrospective (case-control) collaborative study evaluates tendon reflex recordings combined with transcranial magnetic stimulation motor evoked potentials recordings (T-MEPs) at lower limbs in amyotrophic lateral sclerosis (ALS). T-MEPs were recorded in 97 ALS patients distinguished according to their patellar reflex briskness. Patients' electrophysiological data were compared with values measured in 60 control patients matched for age and height. Correlations studies between parameters or with some patients' clinical characteristics were also performed. The central motor conduction time yields the highest sensitivity (82%) and specificity (93%), allowing twice more upper motor neuron (UMN) dysfunction detection than clinical examination, and being more altered in late stages of the disease. The T response to MEP response amplitude ratio (T/MEP ar) is nearly as sensitive to detect ALS and better identifies abnormal hyperreflexia. It is not correlated with evolutive stage, contrarily to conduction time-related parameters. In addition, T-MEPs detect asymmetries escaping clinical examination. The corticospinal conduction to lower limbs is slowed in ALS. The T/MEP ar helps deciding when patellar reflexes are abnormal in a given patient suspected of ALS. The T-MEP technique provide powerful electrophysiological biomarkers of UMN involvement in ALS. This simple and painless procedure introduces the clinically useful concept of electrophysiological hyperreflexia and might be expanded to future exploration of proximal upper limbs and bulbar territories. [ABSTRACT FROM AUTHOR]

• Long Covid patients with fatigue and cognitive problems show impairment of cortical GABA B activity and reduced plasticity in primary motor cortex. • Co-ultramicronized palmitoylethanolamide with luteolin (PEA-LUT) 700 + 70 mg bid for 8 weeks restores GABA B neurotransmission and cortical plasticity. • PEA-LUT is a candidate for the treatment of long Covid patients. Transcranial magnetic stimulation (TMS) studies showed that patients with cognitive dysfunction and fatigue after COVID-19 exhibit impaired cortical GABA B- ergic activity, as revealed by reduced long-interval intracortical inhibition (LICI). Aim of this study was to test the effects of co-ultramicronized palmitoylethanolamide/luteolin (PEA-LUT), an endocannabinoid-like mediator able to enhance GABA-ergic transmission and to reduce neuroinflammation, on LICI. Thirty-nine patients (26 females, mean age 49.9 ± 11.4 years, mean time from infection 296.7 ± 112.3 days) suffering from persistent cognitive difficulties and fatigue after mild COVID-19 were randomly assigned to receive either PEA-LUT 700 mg + 70 mg or PLACEBO, administered orally bid for eight weeks. The day before (PRE) and at the end of the treatment (POST), they underwent TMS protocols to assess LICI. We further evaluate short-latency afferent inhibition (SAI) and long-term potentiation (LTP)-like cortical plasticity. Patients treated with PEA-LUT but not with PLACEBO showed a significant increase of LICI and LTP-like cortical plasticity. SAI remained unaffected. Eight weeks of treatment with PEA-LUT restore GABA B activity and cortical plasticity in long Covid patients. This study confirms altered physiology of the motor cortex in long COVID-19 syndrome and indicates PEA-LUT as a candidate for the treatment of this post-viral condition. [ABSTRACT FROM AUTHOR]

• The paper corrects discrepancies in the difference equations of the previously suggested model of theta-burst stimulation. • The corrected stages are consistently calibrated to experimental data to serve for quantitative analysis. • This work improves the model accuracy in various conditions and secures the model that underlies a rich body of research. Calcium dependency is presently an essential assumption in modelling the neuromodulatory effects of transcranial magnetic stimulation. Y.Z. Huang et al. developed the first neuromodulation model to explain the bidirectional effects of theta-burst stimulation (TBS) based on the postsynaptic intracellular calcium concentration elevation. However, we discover that the published computer code is not consistent with the model formulation, neither do the parameters and derived plots consequently match the formulations. Here we intend to fix the computer code and re-calibrate the model. We corrected the affected difference equations and re-calibrated the revised model with experimental data using non-convex optimisation based on a L 2 penalty. The revised model outperforms the initial model in characterising the relative motor-evoked potential levels of TBS-induced after-effects in various conditions. We corrected the inconsistencies in the previous model and computer code and provided a complete calibration to support the research that is based on it. This work improves the accuracy and secures the scope of the model, which is necessary to retain a rich body of research resulting from the model. Furthermore, this model provides both a quantitative model for several parameters of TBS and a basic model foundation for future refinement. [ABSTRACT FROM AUTHOR]

• Non-invasive brain stimulation can effectively enhance cognition in Alzheimer's disease dementia. • The Neuro-ADTM and left DLPFC rTMS/tDCS have been the most effective protocols. • The beneficial cognitive effects of rTMS outlast for one month. Alzheimer's disease dementia (AD) and its preclinical stage, mild cognitive impairment (MCI), are critical issues confronting the aging society. Non-invasive brain stimulation (NIBS) techniques have the potential to be effective tools for enhancing cognitive functioning. The main objective of our meta-analysis was to quantify and update the status of the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) and Transcranial Direct Current Stimulation (tDCS) when applied in AD and MCI. The systematic literature search was conducted in PubMed and Web of Science according to PRISMA statement. Pooled effect sizes (Hedges' g) from 32 studies were analyzed using random effect models. We found both, rTMS and tDCS to have significant immediate cognition-enhancing effect in AD with rTMS inducing also beneficial long-term effects. We found no evidence for synergistic effect of cognitive training with NIBS. In AD a clinical recommendation can be made for NEURO-ADTM system and for high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) as probably effective protocols (B-level of evidence) and for anodal tDCS over the left DLPFC as a possibly effective. According to scientific literature, NIBS may be an effective method for improving cognition in AD and possibly in MCI. [ABSTRACT FROM AUTHOR]

• Sensorimotor integration can be explored through a conditioned transcranial magnetic stimulation (TMS) protocol -i.e., short-latency afferent inhibition (SAI). • Coupling peripheral and cortical stimulation at early interstimulus intervals may modulate muscle response. • Afferent inhibition is produced both through a direct (thalamus-motor cortex) and indirect (thalamus-somatosensory-motor cortex) pathway. Sensorimotor integration is a crucial process for adaptive behaviour and can be explored non-invasively with a conditioned transcranial magnetic stimulation (TMS) paradigm - i.e. short-latency afferent inhibition (SAI). To gain insight into the sensorimotor integration phenomenon, we used two different approaches to combine peripheral and cortical stimulation in the SAI paradigm, measuring not only the latency of low frequency somatosensory evoked potentials (SEPs) but also the peaks of high frequency oscillations (HFOs) underlying SEPs. The interstimulus intervals (ISIs) between the electrical stimulation of the median nerve and the motor cortex magnetic stimulation were determined relative to the latency of the earliest SEPs cortical potential (N20) or the HFOs peaks. In particular, the first and last negative and positive peaks of HFOs were extracted through a custom-made MATLAB script. Thirty-three healthy subjects participated in this study. We found out that muscle responses after TMS were suppressed when ISIs were comprised between –1 to +3 ms relative to the N20 peak and at all ISIs relative to HFOs peaks, except for the first negative peak. Coupling peripheral and cortical stimulation at early interstimulus intervals – before the SEPs N20 peak - may modulate muscle response. Our findings confirm that afferent inhibition is produced both through a direct (thalamus-motor cortex) and indirect (thalamus-somatosensory-motor cortex) pathway. [ABSTRACT FROM AUTHOR]

• Anodal transcranial direct current stimulation is associated with a cortical disinhibtion in subacute stroke patients. • The degree of cortical disinhibition correlates with motor performance. • Cathodal transcranial direct current stimulation of the affected hemisphere did not modulate motor excitability. To characterize motor excitability changes and changes of motor performance induced by a single anodal and cathodal transcranial direct current stimulation (tDCS) session in stroke patients. Twenty subacute stroke patients participated. Motor performance was tested with the Box and Block Test [BBT]. Motor cortex excitability (short interval intracortical inhibition [SICI], intracortical facilitation [ICF], long interval intracortical inhibition [LICI]) was examined by paired pulse transcranial magnetic stimulation before and after a single tDCS session (20 minutes, 1,0 mA). On two different occasions, patients received anodal and cathodal tDCS over the affected hemisphere. TMS recordings were taken from both hands consecutively. Anodal tDCS significantly reduced SICI without changing ICF or LICI. Cathodal tDCS did not change motor excitability. Both types of tDCS did not alter motor performance. Even prior to anodal tDCS, SICI in the affected hemisphere was lower than in the unaffected hemisphere and was correlated with BBT changes after anodal tDCS. Anodal, but not cathodal tDCS specifically modulated intracortical inhibitory circuits, leading to a disinhibition. The results amplify our knowledge on excitability modulations of tDCS in stroke patients. [ABSTRACT FROM AUTHOR]

• Transcranial magnetic stimulation evoked potentials (TEPs) are variable with respect to methodological parameters of the study. • Five categories have been separated based on the main experimental parameters over two cortical regions in a healthy population. • A meta-analysis has been performed in each category, resulting in approximate statistical measures for every TEP peak amplitude. This meta-analysis aimed to synthesize the existing literature on how different parameters of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG) modulate the amplitudes of TMS-evoked potentials (TEPs). A comprehensive search was run in PubMed and completed by Google Scholar to find articles studying healthy participants who underwent single pulse TMS-EEG sessions over their left primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC). The amplitudes of the most commonly investigated TEP peaks for DLPFC stimulation (positives: 25, 60, 185 ms, negatives: 40, 100 ms) and M1 stimulation (positives: 30, 55,180 ms and negatives: 15, 45, 100, 280 ms) were extracted from studies. Cohen's d effect sizes were obtained in five independent categories that were stratified based on the stimulation, recording, and analyzing parameters. The overall effect sizes and equivalent means and standard deviations were computed within every category. This meta-analysis spotlights the need to rigorously and systematically control for the critical parameters in recording and analyzing TMS-EEG data to make the outcomes of further studies more comparable to the current body of literature. The study demonstrates the possibility of reliably measuring TEPs by offering approximate ranges for every TEP peak in the most commonly targeted areas of DLPFC and M1. [ABSTRACT FROM AUTHOR]

• Corticospinal neurons were tested with transcranial magnetic stimulation with posteriorly and anteriorly directed currents. • Topographic distribution of cortical potentials recorded by electroencephalography changed with different current directions. • Activation of corticospinal neurons is affected by various neuronal elements with inputs from different cortical areas. To investigate the neuronal elements involved in the activation of corticospinal neurons in the primary motor cortex (M1). We studied 10 healthy subjects. Cortical evoked potentials with different components induced by monophasic transcranial magnetic stimulation (TMS) in anterior-posterior and posterior-anterior currents recorded with electroencephalography (EEG) were analyzed. EEG signatures with P25 and N45 components recorded at the C3 electrode with posterior-anterior current were larger than those with anterior-posterior current, while the signatures with P180 and N280 components recorded at the FC1 electrode with anterior-posterior current were larger than those with posterior-anterior current. The source localization analysis revealed that the cortical evoked potential with anterior-posterior current distributed both in the M1 and premotor cortex while that with posterior-anterior current only located in the M1. We conclude that the activation of corticospinal pyramidal neurons in the M1 is affected by various neuronal elements including the local intracortical circuits in the M1 and inputs from premotor cortex with different sensitivities to TMS in opposite current directions. Our finding helped answer a longstanding question about how the corticospinal pathway from the M1 is functionally organized and activated. [ABSTRACT FROM AUTHOR]

• A TMS questionnaire, TMSens_Q, was developed to report secondary effects following TMS application. • A Delphi procedure was used to reach a consensus on items among international TMS experts. • The TMS questionnaire could improve the quality of data reporting in TMS studies. Transcranial magnetic stimulation (TMS) has been widely used in both clinical and research practice. However, TMS might induce unintended sensations and undesired effects as well as serious adverse effects. To date, no shared forms are available to report such unintended effects. This study aimed at developing a questionnaire enabling reporting of TMS unintended effects. A Delphi procedure was applied which allowed consensus among TMS experts. A steering committee nominated a number of experts to be involved in the Delphi procedure. Three rounds were conducted before reaching a consensus. Afterwards, the questionnaire was publicized on the International Federation of Clinical Neurophysiology website to collect further suggestions by the wider scientific community. A last Delphi round was then conducted to obtain consensus on the suggestions collected during the publicization and integrate them in the questionnaire. The procedure resulted in a questionnaire, that is the TMSens_Q, applicable in clinical and research settings. Routine use of the structured TMS questionnaire and standard reporting of unintended TMS effects will help to monitor the safety of TMS, particularly when applying new protocols. It will also improve the quality of data collection as well as the interpretation of experimental findings. [ABSTRACT FROM AUTHOR]

• Further evidence of hyperplasticity in the brain of individuals with autism. • 'Mechanism-driven' rTMS that potentiates brain inhibitory mechanisms could stabilize cortical hyperplasticity in autism. • 'Mechanism-driven' rTMS innovations hold promise for developing plasticity-based novel interventions for autism. Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) – which potentiates brain inhibitory mechanisms – would 'stabilize' hyperplasticity. Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS. Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults. We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be 'stabilized' using rTMS. Such 'stabilizing' effect of rTMS on LTP was not observed, likely due to small sample size or a more specific 'attenuating' effect of rTMS on LTD, compared to LTP. These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of 'mechanism-driven' rTMS. [ABSTRACT FROM AUTHOR]

• Sensory-evoked activity can contaminate TMS-evoked potentials (TEPs). • A spatially matched sensory sham showed contamination of TEPs > 55 ms post-stimulation. • Contamination was not explained by a linear sum of auditory and somatosensory stimulation alone. It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two. Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants. Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone. Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both. Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation. [ABSTRACT FROM AUTHOR]

• TMS primarily targets the gyri at the hemispheric surface due to limited depth penetration. • The direct response to TMS is complex, involving a mixture of neuronal populations. • Myelinated axon terminals of pyramidal cells and inhibitory interneurons in the crown of the gyri constitute low-threshold targets for TMS. • Neuronal excitation propagates along axons and across synapses from the primary stimulation site to connected regions in a state-dependent fashion. • TMS always causes substantial peripheral somatosensory and auditory co-stimulation. Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool. [ABSTRACT FROM AUTHOR]

• Repetitive Transcranial Magnetic Stimulation (rTMS) can facilitate rehabilitation of language skills in post-stroke aphasia. • Individual clinical characteristics, rTMS parameters, and language skills moderated treatment effects. • Low frequency rTMS administered 20–40 min per day over right BA45 improved language abilities for up to 12 months. This meta-analysis examined the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in treating post-stroke aphasia with a goal to identify parameters that are associated with successful treatment outcomes. Following PRISMA guidelines, ten electronic databases were searched from inception till June 4th 2020. A total of 24 studies (out of 1971 records) with 567 participants met selection criteria and were included in the meta-analysis. The overall pooled meta-analysis revealed a significant medium effect size in favor of rTMS treatment: Standard mean difference (SMD) of 0.655 (95% CI = [0.481, 0.830], z = 7.369, p < 0.001). Moderator subgroup analyses indicated that participants' clinical characteristics and rTMS parameters moderated treatment effects. The strongest effects were observed for naming, followed by speech production, repetition and comprehension. The results indicate that with 10 to 15 sessions of 1-Hz rTMS administered 20–40 min per day over right BA45 (Brodmann's area 45), significant language improvements can be observed for up to 12 months. Our findings suggest that the rTMS technique can enhance rehabilitation of language skills in post-stroke aphasia when administered according to the established safety parameters. Our results have implications for treatment of post-stroke aphasia. In subacute aphasia, low frequency rTMS over right BA45 improved naming, repetition, speech fluency and writing but not comprehension, whereas in chronic aphasia naming and speech production improved, but repetition and comprehension showed smaller gains. [ABSTRACT FROM AUTHOR]