An exploratory study of the damage markers NfL, GFAP, and t-Tau, in cerebrospinal fluid and other findings from a patient cohort enriched for suspected autoimmune psychiatric disease.

There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses.

Evoked potentials after autologous hematopoietic stem cell transplantation for multiple sclerosis.

OBJECTIVE: To investigate the effect of autologous hematopoietic stem cell transplantation (AHSCT) on functional aspects of the nervous system assessed by visual (VEP), somatosensory (SEP), and motor (MEP) evoked potentials in patients with relapsing-remitting multiple sclerosis. BACKGROUND: Several studies have demonstrated the efficacy of AHSCT on inflammatory activity and disability progression in patients with multiple sclerosis. However, the impact of AHSCT on evoked potentials has not been evaluated before. METHODS: Twelve AHSCT-treated patients from Uppsala University Hospital were consecutively recruited. Evoked potentials (EP) were collected at baseline and two follow-up visits, 3 and 12 months post-AHSCT. We calculated a composite EP score for each participant and compared it between different time points. RESULTS: The median total EP score decreased from 5 at baseline, to 2.5 at 12 months post-ASHCT (p = 0.008). A significant improvement in tibial SEP (tSEP) latencies was observed (42.7 vs 41.5 ms, p < 0.001), with a similar trend for MEP latencies 12 months post-ASHCT. No significant changes in median SEP or VEP latencies were observed. CONCLUSIONS: Treatment with AHSCT was associated with improved transmission in some central nervous system pathways in multiple sclerosis patients.

Monitoring transcranial direct current stimulation induced changes in cortical excitability during the serial reaction time task.

The measurement of the motor evoked potential (MEP) amplitudes using single pulse transcranial magnetic stimulation (TMS) is a common method to observe changes in motor cortical excitability. The level of cortical excitability has been shown to change during motor learning. Conversely, motor learning can be improved by using anodal transcranial direct current stimulation (tDCS). In the present study, we aimed to monitor cortical excitability changes during an implicit motor learning paradigm, a version of the serial reaction time task (SRTT). Responses from the first dorsal interosseous (FDI) and forearm flexor (FLEX) muscles were recorded before, during and after the performance of the SRTT. Online measurements were combined with anodal, cathodal or sham tDCS for the duration of the SRTT. Negative correlations between the amplitude of online FDI MEPs and SRTT reaction times (RTs) were observed across the learning blocks in the cathodal condition (higher average MEP amplitudes associated with lower RTs) but no significant differences in the anodal and sham conditions. tDCS did not have an impact on SRTT performance, as would be predicted based on previous studies. The offline before-after SRTT MEP amplitudes showed an increase after anodal and a tendency to decrease after cathodal stimulation, but these changes were not significant. The combination of different interventions during tDCS might result in reduced efficacy of the stimulation that in future studies need further attention.

Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation.

PURPOSE: Transcranial random noise stimulation (tRNS) can increase the excitability of hand area of the primary motor cortex (M1). The aim of this study was to compare the efficacy of tRNS and transcranial direct current stimulation (tDCS) on the leg motor cortex. METHOD: Ten healthy subjects received anodal, cathodal tDCS, tRNS and sham stimulation for 10 min using 2 mA intensity during separate experimental sessions. Single pulse transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) measurements were used to assess motor cortical excitability changes after the stimulation. RESULTS: Similar to the hand area, we found that both tRNS and anodal tDCS induced an increase of the amplitude of the MEPs. Anodal tDCS induced a constant gradual increase of corticospinal excitability until 60 min post-stimulation, whereas the effect of tRNS was immediate with a duration of 40 min following stimulation. The cathodal tDCS induced decrease in MEP amplitude did not reach statistical significance. CONCLUSION: Our results suggest that although the leg area has a deeper position in the cortex compared to the hand area, it can be reached by weak transcranial currents. Both anodal tDCS and tRNS had comparable effect on cortical excitability.

Minocycline exerts acute inhibitory effects on cerebral cortex excitability in humans.

Minocycline has efficacy to alleviate seizure activity in animal models of epilepsy. Among other mechanisms it has been postulated that minocycline can inhibit microglial activation and develop beneficial effects by decreasing glutamate excitotoxicity. To explore acute effects of minocycline on human motor cortex excitability we used single- and paired-pulse transcranial magnetic stimulation in 12 healthy subjects 4h after a single oral dose of 200mg minocycline or placebo was administered in a randomised, double-blind, placebo-controlled crossover design. Mean cortical silent period, an inhibitory parameter of predominantly intracortical origin, was prolonged after minocycline compared to placebo, while other TMS parameters of cortical excitability remained unchanged. The results demonstrate that a particular parameter of cortical inhibition is rapidly increased after a single oral dose of minocycline in humans.

Effects of lacosamide and carbamazepine on human motor cortex excitability: a double-blind, placebo-controlled transcranial magnetic stimulation study.

PURPOSE: Lacosamide (LCM) and carbamazepine (CBZ) are antiepileptic drugs both acting on neuronal voltage-gated sodium channels. Patch-clamp studies demonstrated significant differences in how LCM and CBZ affect neuronal membrane excitability. Despite valuable information patch-clamp studies provide, they also comprise some constraints. For example, little is known about effects of LCM on intracortical synaptic excitability. In contrast, transcranial magnetic stimulation (TMS) can describe drug-induced changes at the system level of the human cerebral cortex. METHODS: The present study was designed to explore dose-depended effects of LCM and effects of CBZ on motor cortex excitability with TMS in a randomized, double-blind, placebo-controlled crossover trial in healthy human subjects. Subjects received 600 mg CBZ, 200 mg LCM, 400 mg LCM or placebo preceding TMS measurements. RESULTS: Compared to placebo, TMS motor thresholds were significantly increased after carbamazepine and lacosamide, with a trend for a dose dependent effect of lacosamide. Both, carbamazepine and lacosamide did not affect TMS parameters of intracortical synaptic excitability. CONCLUSIONS: TMS measurements suggest that lacosamide and carbamazepine predominantly act on neuronal membrane excitability.

Mechanisms of human motor cortex facilitation induced by subthreshold 5-Hz repetitive transcranial magnetic stimulation.

Our knowledge about the mechanisms of human motor cortex facilitation induced by repetitive transcranial magnetic stimulation (rTMS) is still incomplete. Here we used pharmacological conditioning with carbamazepine, dextrometorphan, lorazepam, and placebo to elucidate the type of plasticity underlying this facilitation, and to probe if mechanisms reminiscent of long-term potentiation are involved. Over the primary motor cortex of 10 healthy subjects, we applied biphasic rTMS pulses of effective posterior current direction in the brain. We used six blocks of 200 pulses at 5-Hz frequency and 90% active motor threshold intensity and controlled for corticospinal excitability changes using motor-evoked potential (MEP) amplitudes and latencies elicited by suprathreshold pulses before, in between, and after rTMS. Target muscle was the dominant abductor digiti minimi muscle; we coregistered the dominant extensor carpi radialis muscle. We found a lasting facilitation induced by this type of rTMS. The GABAergic medication lorazepam and to a lesser extent the ion channel blocker carbamazepine reduced the MEP facilitation after biphasic effective posteriorly oriented rTMS, whereas the N-methyl-d-aspartate receptor-antagonist dextrometorphan had no effect. Our main conclusion is that the mechanism of the facilitation induced by biphasic effective posterior rTMS is more likely posttetanic potentiation than long-term potentiation. Additional findings were prolonged MEP latency under carbamazepine, consistent with sodium channel blockade, and larger MEP amplitudes from extensor carpi radialis under lorazepam, suggesting GABAergic involvement in the center-surround balance of excitability.

Opposite optimal current flow directions for induction of neuroplasticity and excitation threshold in the human motor cortex.

BACKGROUND: Directional sensitivity is relevant for the excitability threshold of the human primary motor cortex, but its importance for externally induced plasticity is unknown. OBJECTIVE: To study the influence of current direction on two paradigms inducing neuroplasticity by repetitive transcranial magnetic stimulation (rTMS). METHODS: We studied short-lasting after-effects induced in the human primary motor cortex of 8 healthy subjects, using 5 Hz rTMS applied in six blocks of 200 pulses each, at 90% active motor threshold. We controlled for intensity, frequency, waveform and spinal effects. RESULTS: Only biphasic pulses with the effective component delivered in an anterioposterior direction (henceforth posteriorly directed) in the brain yielded an increase of motor-evoked potential (MEP) amplitudes outlasting rTMS. MEP latencies and F-wave amplitudes remained unchanged. Biphasic pulses directed posteroanterior (i.e. anteriorly) were ineffective, as were monophasic pulses from either direction. A 1 Hz study in a group of 12 healthy subjects confirmed facilitation after posteriorly directed biphasic pulses only. CONCLUSIONS: The anisotropy of the human primary motor cortex is relevant for induction of plasticity by subtreshold rTMS, with a current flow opposite to that providing lowest excitability thresholds. This is consistent with the idea of TMS primarily targeting cortical columns of the phylogenetically new M1 in the anterior bank of the central sulcus. For these, anteriorly directed currents are soma-depolarizing, therefore optimal for low thresholds, whereas posteriorly directed currents are soma-hyperpolarizing, likely dendrite-depolarizing and bested suited for induction of plasticity. Our findings should help focus and enhance rTMS effects in experimental and clinical settings.

Carbamazepine reduces short-interval interhemispheric inhibition in healthy humans.

OBJECTIVE: We sought to elucidate the influence of centrally active drugs on interhemispheric inhibition (IHI) between primary motor cortices in healthy humans. METHODS: We therefore studied IHI before and 2h after intake of a single oral dose of carbamazepine, dextrometorphane, lorazepam, or placebo and compared it with the well known results for short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Drugs were tested in separate sessions and in random order. RESULTS: While SICI and ICF were not altered by carbamazepine, IHI was reduced at the interstimulus interval of 8 ms. Dextrometorphane tended to enhance SICI and to reduce ICF and had no effect on IHI. Lorazepam reduced ICF as expected and enhanced IHI at the long intervals of 50 and 80ms. A moderate trend for interhemispheric facilitation was inconsistently observed at the interval 2 ms and blocked by carbamazepine. In addition, carbamazepine increased the motor threshold. CONCLUSIONS: We conclude that circuits mediating short interstimulus intervals of IHI are susceptible to sodium channel blockade. SIGNIFICANCE: The results increase our knowledge of interhemispheric transmission.

Circadian modulation of GABA-mediated cortical inhibition.

Circadian rhythms exert powerful influence on various aspects of human physiology and behavior. Here, we tested changes of human cerebral cortex excitability over the course of the day with transcranial magnetic stimulation (TMS). At different times of the day, intracortical and corticospinal excitability of the primary motor cortex (M1) was evaluated in 15 healthy subjects by TMS of left M1. While motor thresholds, short-interval intracortical inhibition and facilitation and input/output curves remained unchanged, we found that a specific form of γ-aminobutyric acid (GABA)-mediated intracortical inhibition, revealed by long-interval intracortical inhibition and cortical silent periods, progressively decreased during the course of the day. Additional experiments demonstrated that morning inhibition persisted irrespective of previous sleep or sleep deprivation. Corticotropin-releasing hormone (CRH) infusions in the evening lead to morning cortisol levels but did not restore levels of morning inhibition, whereas suppression of endogenous CRH release by repeated oral dexamethasone intake over 24 h prevented morning inhibition. The findings suggest a specific modulation of GABAergic motor cortex inhibition within the circadian cycle, possibly linked to the CRH system, and may indicate a neurobiological basis for variable neuroplasticity over the course of the day.

Right-shift for non-speech motor processing in adults who stutter.

INTRODUCTION: In adults who do not stutter (AWNS), the control of hand movement timing is assumed to be lateralized to the left dorsolateral premotor cortex (PMd). In adults who stutter (AWS), the network of speech motor control is abnormally shifted to the right hemisphere. Motor impairments in AWS are not restricted to speech, but extend to non-speech orofacial and finger movements. We here investigated the lateralization of finger movement timing control in AWS. METHODS: We explored PMd function in 14 right-handed AWS and 15 age matched AWNS. In separate sessions, they received subthreshold repetitive transcranial magnetic stimulation (rTMS) for 20 min at 1Hz over the left or right PMd, respectively. Pre- and post-stimulation participants were instructed to synchronize their index finger taps of either hand with an isochronous sequence of clicks presented binaurally via earphones. Synchronization accuracy was measured to quantify the effect of the PMd stimulation. RESULTS: In AWNS inhibition of left PMd affected synchronization accuracy of the left hand. Conversely, in AWS TMS over the right PMd increased the asynchrony of the left hand. CONCLUSIONS: The present data indicate an altered functional connectivity in AWS in which the right PMd seems to be important for the control of timed non-speech movements. Moreover, the laterality-shift suggests a compensatory role of the right PMd to successfully perform paced finger tapping.

Efficacy of EMG-triggered electrical arm stimulation in chronic hemiparetic stroke patients.

PURPOSE: EMG-triggered electrostimulation (EMG-ES) may improve the motor performance of affected limbs of hemiparetic stroke patients even in the chronic stage. This study was designed to characterize cortical activation changes following intensified EMG-ES in chronic stroke patients and to identify predictors for successful rehabilitation depending on disease severity. METHODS: We studied 9 patients with severe residual hemiparesis, who underwent 8 weeks of daily task-orientated multi-channel EMG-ES of the paretic arm. Before and after treatment, arm function was evaluated clinically and cortical activation patterns were assessed with functional MRI (fMRI) and/or transcranial magnetic stimulation (TMS). RESULTS: As response to therapy, arm function improved in a subset of patients with more capacity in less affected subjects, but there was no significant gain for those with Box & Block test values below 4 at inception. The clinical improvement, if any, was accompanied by an ipsilesional increase in the sensorimotor cortex (SMC) activation area in fMRI and enhanced intracortical facilitation (ICF) as revealed by paired TMS. The SMC activation change in fMRI was predicted by the presence or absence of motor-evoked potentials (MEPs) on the affected side. CONCLUSIONS: The present findings support the notion that intensified EMG-ES may improve the arm function in individual chronic hemiparetic stroke patients but not in more severely impaired individuals. Functional improvements are paralleled by increased ipsilesional SMC activation and enhanced ICF supporting neuroplasticity as contributor to rehabilitation. The clinical score at inception and the presence of MEPs have the best predictive potential.

H-coil: Induced electric field properties and input/output curves on healthy volunteers, comparison with a standard figure-of-eight coil.

OBJECTIVE: To acquire information about the physical properties and physiological effects of the H-coil. METHODS: We used a robotized system to measure the electric field (E-field) generated by a H-coil prototype and compared it with a standard figure-of-eight coil. To explore the physiological properties of the coils, input/output curves were recorded for the right abductor digiti minimi muscle (ADM) as target muscle. To explore focality of stimulation, simultaneous recordings were performed for the left ADM, right abductor pollicis brevis (APB), extensor digitorum communis (EDC) and biceps brachii (BB) muscles. RESULTS: Physical measurements of the H-coil showed four potentially stimulating foci, generating different electric field intensities along two different spatial orientations. RMT was significantly lower for H-coil- as compared to figure-of-eight coil stimulation. When stimulation intensity for the input-output curve was determined by percent of maximum stimulator output, the H-coil produced larger MEPs in the right ADM, as compared to the figure-of-eight coil, due to the larger relative enhancement of stimulation intensity of the H-coil. When stimulation intensity was adjusted to RMT, MEPs elicited at the right ADM were larger for figure-of-eight coil than for H-coil stimulation, while this relation was reversed for distant non-target muscles, with low stimulation intensities. With high stimulation intensities, the H-coil elicited larger MEPs for all tested muscles. Onset latency of the MEPs was never shorter for H-coil than for figure-of-eight coil stimulation of the target muscles. CONCLUSIONS: These results are in favor for a non-focal, but not deeper effect of the H-coil, as compared to a figure-of-eight coil. SIGNIFICANCE: This is the first neurophysiological study exploring the focality and depth of stimulation delivered by the H-coil systematically in humans. We found no advantage of this coil with regard to depth of stimulation in comparison to the figure-of-eight coil. Future studies have to show if the non-focality of this coil differs relevantly from that of other non-focal coils, e.g. the round coil.

Training effects outweigh effects of single-session conventional rTMS and theta burst stimulation in PD patients.

BACKGROUND: Focal single-session repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been claimed to be capable of improving motor function in Parkinson's disease. OBJECTIVE: The authors sought to determine which type of rTMS protocol holds the highest potential for future therapeutic application. METHODS: Twenty-two patients with Parkinson's disease received 5 different rTMS protocols on 5 consecutive days in a pseudorandomized and counterbalanced order either in the defined OFF condition or with their usual medication. The protocols tested in the present study included 2 conventional rTMS protocols (0.5 and 10 Hz) as well as the recently introduced theta burst stimulation (cTBS, iTBS) and a sham condition. Cortical excitability, motor performance (pointing movement, pronation-supination, Purdue Pegboard Test, walking), and mood were assessed before and after each session. RESULTS: The authors observed motor training from days 1 to 4, particularly in the group on dopaminergic medication. None of the rTMS paradigms excelled placebo stimulation. The only exception was the Purdue Pegboard Test, in which all active stimulation paradigms yielded slightly stronger effects than sham stimulation. CONCLUSIONS: Within a single session, no clinically relevant difference in the rTMS protocols could be detected. Training effects outweigh and may have masked rTMS effects, particularly in the group on dopaminergic mediation.

The effect of rTMS over left and right dorsolateral premotor cortex on movement timing of either hand.

It has been suggested that the left dorsolateral premotor cortex (dPMC) controls timing abilities of either hand. To further clarify its functional significance for movement timing, low-frequency repetitive transcranial magnetic stimulation (rTMS) was applied over the left and right dPMC, respectively, while subjects performed an auditorily paced finger-tapping task with each hand. rTMS over the left dPMC decreased tapping accuracy of both hands, whereas no behavioural effects occurred following right dPMC stimulation. To elucidate the time window in which left dPMC TMS disturbs synchronization abilities, pairs of TMS pulses were applied over the left dPMC and the left anterior parietal cortex serving as control condition. TMS pulses were applied randomly at 40 ms, 80 ms, 120 ms, 160 ms, 200 ms and 240 ms before pacer onset, as taps precede the pacing signal for about 20-60 ms. Again, the analysis revealed that TMS over the left dPMC disturbed synchronization abilities of either hand; however, this effect was shown at different times suggesting that the left dPMC affects the right M1 via at least one additional relay station. The present data support the hypothesis that the left dPMC is crucial for accurate timing of either hand. Additionally, they reveal a piece of evidence that the left dPMC affects the left hand not via a direct left dPMC-right M1 connection.

Dopaminergic potentiation of rTMS-induced motor cortex inhibition.

BACKGROUND: Experiments in animal models suggest that neuronal plasticity can be enhanced by dopaminergic receptor activation. The present study tested whether stimulation-induced plasticity of human motor cortex after low-frequency repetitive transcranial magnetic stimulation (rTMS) could be potentiated by a single oral dose of the combined D1/D2 receptor agonist pergolide. METHODS: In a randomized, double-blind, placebo-controlled cross-over design, nine healthy young volunteers received .125 mg pergolide or placebo 2 hours before 1 Hz rTMS was applied for 20 min to the left primary motor cortex. In a control experiment 7 subjects received .125 mg pergolide 2 hours before sham rTMS. We used single-pulse TMS at rest to assess corticospinal excitability before and up to 24 min after rTMS. RESULTS: Suppression of corticospinal excitability by 1 Hz rTMS was more pronounced after pergolide intake compared with placebo and lasted approximately 20 min after pergolide but only 5 min after placebo. No change of corticospinal excitability could be observed when sham rTMS was performed after pergolide intake. CONCLUSIONS: The results suggest a possible role for dopaminergic potentiation of rTMS-induced neuroplasticity in experimental or therapeutic applications and should be considered when rTMS is applied in patients under medication with dopamine agonists or antagonists.