Increased signal diversity/complexity of spontaneous EEG, but not evoked EEG responses, in ketamine-induced psychedelic state in humans.

How and to what extent electrical brain activity reflects pharmacologically altered states and contents of consciousness, is not well understood. Therefore, we investigated whether measures of evoked and spontaneous electroencephalographic (EEG) signal diversity are altered by sub-anaesthetic levels of ketamine compared to normal wakefulness, and how these measures relate to subjective experience. High-density 62-channel EEG was used to record spontaneous brain activity and responses evoked by transcranial magnetic stimulation (TMS) in 10 healthy volunteers before and during administration of sub-anaesthetic doses of ketamine in an open-label within-subject design. Evoked signal diversity was assessed using the perturbational complexity index (PCI), calculated from EEG responses to TMS perturbations. Signal diversity of spontaneous EEG, with eyes open and eyes closed, was assessed by Lempel Ziv complexity (LZc), amplitude coalition entropy (ACE), and synchrony coalition entropy (SCE). Although no significant difference was found in TMS-evoked complexity (PCI) between the sub-anaesthetic ketamine condition and normal wakefulness, all measures of spontaneous EEG signal diversity (LZc, ACE, SCE) showed significantly increased values in the sub-anaesthetic ketamine condition. This increase in signal diversity correlated with subjective assessment of altered states of consciousness. Moreover, spontaneous signal diversity was significantly higher when participants had eyes open compared to eyes closed, both during normal wakefulness and during influence of sub-anaesthetic ketamine. The results suggest that PCI and spontaneous signal diversity may reflect distinct, complementary aspects of changes in brain properties related to altered states of consciousness: the brain's capacity for information integration, assessed by PCI, might be indicative of the brain's ability to sustain consciousness, while spontaneous complexity, as measured by EEG signal diversity, may be indicative of the complexity of conscious content. Thus, sub-anaesthetic ketamine may increase the complexity of the conscious content and the brain activity underlying it, while the level or general capacity for consciousness remains largely unaffected.

Effect of psychotropic drugs on cortical excitability of patients with major depressive disorders: A transcranial magnetic stimulation study.

Transcranial magnetic stimulation (TMS) can be used to evaluate the effects of pharmacological interventions. The aim of this study was to assess the impact of the selective serotonin reuptake inhibitor, sertraline, and the atypical antipsychotic drugs quetiapine and olanzapine, on cortical excitability in unmedicated patients with major depressive disorder (MDD). The study included 45 medication-free MDD patients diagnosed according to DSM V. They were divided randomly into three groups who received a single oral dose of one of the three drugs sertraline (50 mg), quetiapine (100 mg) and olanzapine (10 mg). Psychological evaluation was conducted using the Mini-Mental State Examination (MMSE) and Beck Depression Inventory Scale (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant before and at the time of maximum concentration of drug intake. There was significant increase in excitability of motor cortex after sertraline without changes in GABAB neurotransmission. Quetiapine and olanzapine potentiated inhibitory GABAB neurotransmission (prolongation of cSP); olanzapine additionally prolonged the iSP. Thus TMS can differentiate between the impact of different psychotropic drugs on excitatory and inhibitory transmission in motor cortex.

Effects of antiepileptic drugs on cortical excitability in humans: A TMS-EMG and TMS-EEG study.

Brain responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) are emergent noninvasive markers of neuronal excitability and effective connectivity in humans. However, the underlying physiology of these TMS-evoked EEG potentials (TEPs) is still heavily underexplored, impeding a broad application of TEPs to study pathology in neuropsychiatric disorders. Here we tested the effects of a single oral dose of three antiepileptic drugs with specific modes of action (carbamazepine, a voltage-gated sodium channel (VGSC) blocker; brivaracetam, a ligand to the presynaptic vesicle protein VSA2; tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor) on TEP amplitudes in 15 healthy adults in a double-blinded randomized placebo-controlled crossover design. We found that carbamazepine decreased the P25 and P180 TEP components, and brivaracetam the N100 amplitude in the nonstimulated hemisphere, while tiagabine had no effect. Findings corroborate the view that the P25 represents axonal excitability of the corticospinal system, the N100 in the nonstimulated hemisphere propagated activity suppressed by inhibition of presynaptic neurotransmitter release, and the P180 late activity particularly sensitive to VGSC blockade. Pharmaco-physiological characterization of TEPs will facilitate utilization of TMS-EEG in neuropsychiatric disorders with altered excitability and/or network connectivity.

The effects of a single dose of fluoxetine on practice-dependent plasticity.

OBJECTIVE: To determine whether a single dose of fluoxetine increases corticomotoneuronal excitability, motor performance and practice-dependent plasticity. METHODS: Twelve healthy adults completed this placebo-controlled, pseudo-randomized, double-blind crossover study. Transcranial magnetic stimulation (TMS) was used to assess corticomotoneuronal excitability, and two uni-axial accelerometers measured kinetics of fastest possible ballistic voluntary thumb movements and TMS-evoked thumb movements. Six hours after administration of either 20 mg of the serotonin reuptake inhibitor fluoxetine or placebo, participants practiced ballistic thumb movements in the direction opposite to the TMS-evoked thumb movements. The primary outcome of this study was the proportion of thumb movements that fell within the target-training zone (TTZ) during and for 30 min after the practice. RESULTS: All participants demonstrated practice-dependent plasticity evidenced by an increase of TMS-evoked thumb movements falling into the TTZ (P = 0.045), with no difference between drugs. There was a significant increase in peak acceleration of the practiced voluntary thumb movements (P = 0.002), but no DRUG by TIME interaction. Motor-evoked potential amplitudes were not changed by drug intake or practice. CONCLUSIONS: A single dose of 20 mg of fluoxetine did not enhance corticomotoneuronal excitability, performance of a ballistic thumb movement task, or practice-dependent plasticity in healthy adults. SIGNIFICANCE: Longer administration fluoxetine may be necessary to enhance motor performance and plasticity.

Risperidone increases the cortical silent period in drug-naive patients with first-episode schizophrenia: A transcranial magnetic stimulation study.

OBJECTIVES: Schizophrenia is accompanied by impaired cortical inhibition, as measured by several markers including the cortical silent period (CSP). It is thought that CSP measures gamma-aminobutyric acid receptors B (GABAB) mediated inhibitory activity. But the mutual roles of schizophrenia as a disease and the drugs used for the treatment of psychosis on GABA mediated neurotransmission are not clear. METHODS: We recruited 13 drug-naive patients with first-episode schizophrenia. We used transcranial magnetic stimulation to assess CSP prior to initiating risperidone monotherapy and again four weeks later. At the same time, we rated the severity of psychopathology using the Positive and Negative Syndrome Scale (PANSS). RESULTS: We obtained data from 12 patients who showed a significant increase in CSP, from 134.20±41.81 ms to 162.95±61.98 ms ( p=0.041; Cohen's d=0.544). After the treatment, the PANSS total score was significantly lower, as were the individual subscores ( p<0.05). However, no correlation was found between ΔCSP and ΔPANSS. CONCLUSION: Our study in patients with first-episode schizophrenia demonstrated an association between risperidone monotherapy and an increase in GABAB mediated inhibitory neurotransmission.

Differences in Motor Evoked Potentials Induced in Rats by Transcranial Magnetic Stimulation under Two Separate Anesthetics: Implications for Plasticity Studies.

Repetitive transcranial magnetic stimulation (rTMS) is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs) are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however, results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS), a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when selecting an anesthetic and in interpreting results during prolonged TMS recording.

TMS and drugs revisited 2014.

The combination of pharmacology and transcranial magnetic stimulation to study the effects of drugs on TMS-evoked EMG responses (pharmaco-TMS-EMG) has considerably improved our understanding of the effects of TMS on the human brain. Ten years have elapsed since an influential review on this topic has been published in this journal (Ziemann, 2004). Since then, several major developments have taken place: TMS has been combined with EEG to measure TMS evoked responses directly from brain activity rather than by motor evoked potentials in a muscle, and pharmacological characterization of the TMS-evoked EEG potentials, although still in its infancy, has started (pharmaco-TMS-EEG). Furthermore, the knowledge from pharmaco-TMS-EMG that has been primarily obtained in healthy subjects is now applied to clinical settings, for instance, to monitor or even predict clinical drug responses in neurological or psychiatric patients. Finally, pharmaco-TMS-EMG has been applied to understand the effects of CNS active drugs on non-invasive brain stimulation induced long-term potentiation-like and long-term depression-like plasticity. This is a new field that may help to develop rationales of pharmacological treatment for enhancement of recovery and re-learning after CNS lesions. This up-dated review will highlight important knowledge and recent advances in the contribution of pharmaco-TMS-EMG and pharmaco-TMS-EEG to our understanding of normal and dysfunctional excitability, connectivity and plasticity of the human brain.

Botulinum toxin modulates cortical maladaptation in post-stroke spasticity.

INTRODUCTION: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. METHODS: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. RESULTS: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. CONCLUSION: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity.

Dopamine D2-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients.

Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid ß formation as well as in cognitive decline progression. In particular it has been shown that dopamine D2-like receptors (namely D3 and D2) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D3 and D2 receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D2-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

A new measure of cortical inhibition by mechanomyography and paired-pulse transcranial magnetic stimulation in unanesthetized rats.

Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive tool for measuring cortical inhibition in humans, particularly in patients with disorders of cortical inhibition such as epilepsy. However, ppTMS protocols in rodent disease models, where mechanistic insight into the ppTMS physiology and into disease processes may be obtained, have been limited due to the requirement for anesthesia and needle electromyography. To eliminate the confounding factor of anesthesia and to approximate human ppTMS protocols in awake rats, we adapted the mechanomyogram (MMG) method to investigate the ppTMS inhibitory phenomenon in awake rats and then applied differential pharmacology to test the hypothesis that long-interval cortical inhibition is mediated by the GABA(A) receptor. Bilateral hindlimb-evoked MMGs were elicited in awake rats by long-interval ppTMS protocols with 50-, 100-, and 200-ms interstimulus intervals. Acute changes in ppTMS-MMG were measured before and after intraperitoneal injections of saline, the GABA(A) agonist pentobarbital (PB), and GABA(A) antagonist pentylenetetrazole (PTZ). An evoked MMG was obtained in 100% of animals by single-pulse stimulation, and ppTMS resulted in predictable inhibition of the test-evoked MMG. With increasing TMS intensity, MMG amplitudes increased in proportion to machine output to produce reliable input-output curves. Simultaneous recordings of electromyography and MMG showed a predictable latency discrepancy between the motor-evoked potential and the evoked MMG (7.55 ± 0.08 and 9.16 ± 0.14 ms, respectively). With pharmacological testing, time course observations showed that ppTMS-MMG inhibition was acutely reduced following PTZ (P < 0.05), acutely enhanced after PB (P < 0.01) injection, and then recovered to pretreatment baseline after 1 h. Our data support the application of the ppTMS-MMG technique for measuring the cortical excitability in awake rats and provide the evidence that GABA(A) receptor contributes to long-interval paired-pulse cortical inhibition. Thus ppTMS-MMG appears a well-tolerated biomarker for measuring GABA(A)-mediated cortical inhibition in rats.

GABA and cortical inhibition in motor and non-motor regions using combined TMS-EEG: a time analysis.

OBJECTIVE: The induction of long interval cortical inhibition (LICI) in motor cortex with paired pulse transcranial magnetic stimulation (ppTMS) is an established paradigm for the assessment of cortical inhibition, proposed to be related to GABA(B) receptor inhibitory neurotransmission. This study aimed to further evaluate recent methods of the assessment of LICI in non motor regions with ppTMS and electroencephalography (EEG). METHODS: ppTMS was applied using a single coil to the motor and dorsolateral prefrontal cortex (DLPFC) in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. RESULTS: In the motor cortex, LICI resulted in significant suppression in mean cortical evoked activity on EEG between 75 and 250 ms following delivery of the test stimulus. Maximal inhibition was seen from 50 to 250 ms in DLPFC, and between 50 and 175 ms in the parietal lobe. CONCLUSIONS: ppTMS may be used to produce LICI in several cortical regions with a time course similar to known GABA(B) activity. SIGNIFICANCE: ppTMS induction of LICI can be recorded by combining TMS with EEG and seems to relate to GABA(B) activity.

Differential effect of halothane on motor evoked potentials elicited by transcranial electric or magnetic stimulation in the monkey.

OBJECTIVE: Halothane (HAL) is known to depress motor evoked potentials produced by transcranial magnetic (tcMMEP) or transcranial electric (tcEMEP) stimulation. This study was designed to determine if differences existed between tcEMEP and tcMMEP with increasing HAL concentra- tions. METHODS: tcMMEP and tcEMEP were characterized during 0-2% inspired HAL in 10 adult cynomologous monkeys during a baseline anesthesia with a continuous ketamine infusion. tcEMEP and tcMMEP were assessed by measuring the onset latency (time from stimulation to the initial response), amplitude of the thenar compound action potential response and threshold (relative power required to elicit a response). Cortical stimulation was accomplished using a Cadwell MES-10 (tcMMEP) and Digitimer Dl80 (tcEMEP). RESULTS: The baseline (no HAL) onset latency for tcEMEP (10.68 ms) was significantly shorter than that of tcMMEP (12.28 ms) (P < 0.05). The amplitudes (7,916, 4,858 microV, respectively) were not significantly different (P > 0.112). The onset latency increased and amplitude decreased for both techniques (no significant difference between tcEMEP and tcMMEP) with increase in HAL. All animals lost their responses below 2% HAL. In each animal the tcMMEP was lost at a HAL concentration below or equal to that for tcEMEP. T The ED(50) (where 50% of the animals lost the response) was significantly different between tcMMEP (0.66% HAL) and tcEMEP (1.04% HAL) (P < 0.05). The relative threshold gradually increased for tcEMEP and abruptly increased above 0.4% HAL for tcMMEP. CONCLUSIONS: These differences in sensitivity to HAL are consistent with other studies with intravenous anesthesia and are consistent with the known difference in the physiological mechanisms by which magnetic and electrical stimulation activates the motor cortex.