Non-stimulated Hemisphere Research Articles

Different effects of I-wave periodicity repetitive TMS on motor cortex interhemispheric interaction.

Activity of the neural circuits in the human motor cortex can be probed using transcranial magnetic stimulation (TMS). Changing TMS-induced current direction recruits different cortical neural circuits. I-wave periodicity repetitive TMS (iTMS) substantially modulates motor cortex excitability through neural plasticity, yet its effect on interhemispheric interaction remains unclear. To explore the modulation of interhemispheric interaction by iTMS applied in different current directions. Twenty right-handed healthy young volunteers (aged 27.5 ± 5.0 years) participated in this study with three visits. On each visit, iTMS in posterior-anterior/anterior-posterior direction (PA-/AP-iTMS) or sham-iTMS was applied to the right hemisphere, with corticospinal excitability and intracortical facilitation of the non-stimulated left hemisphere evaluated at four timepoints. Ipsilateral silent period was also measured at each timepoint probing interhemispheric inhibition (IHI). PA- and AP-iTMS potentiated cortical excitability concurrently in the stimulated right hemisphere. Corticospinal excitability of the non-stimulated left hemisphere increased 10 min after both PA- and AP-iTMS intervention, with a decrease in short-interval intracortical facilitation (SICF) observed in AP-iTMS only. Immediately after the intervention, PA-iTMS tilted the IHI balance toward inhibiting the non-stimulated hemisphere, while AP-iTMS shifted the balance toward the opposite direction. Our findings provide systematic evidence on the plastic modulation of interhemispheric interaction by PA- and AP-iTMS. We show that iTMS induces an interhemispheric facilitatory effect, and that PA- and AP-iTMS differs in modulating interhemispheric inhibition.

Effect of Single Session of Anodal M1 Transcranial Direct Current Stimulation-TDCS-On Cortical Hemodynamic Activity: A Pilot Study in Fibromyalgia.

Transcranial direct current stimulation (TDCS) on the primary motor cortex (M1) has been reported to be effective in fibromyalgia (FM). Our previous works have shown hypometabolism of motor networks in FM using Functional Near Infrared Spectroscopy (fNIRS), which could contribute to pain symptoms. To investigate if a single Transcranial Direct Current Stimulation (TDCS) session can restore the reduced metabolism expected in FM patients, we compared metabolic activity in FM patients and controls during a finger-tapping task in basal condition, sham condition, and under anodal TDCS on M1. During the finger tapping task, a continuous wave 20 channel fNIRS system was placed across the bilateral central-frontal areas in 22 healthy controls and 54 FM patients. Subjects were randomly assigned to real TDCS or sham stimulation. The finger-tapping slowness did not change after real and sham stimulation. After real TDCS stimulation, FM patients showed an increased activation of cortical motor regions (t-statistic = -2.5246, p-value = 0.0125 for the stimulated hemisphere and t-statistic = -4.6638, p-value = 0.0001 for the non-stimulated hemisphere). The basal differences between FM and controls reverted after real TDCS, while this effect was not observed for sham stimulation. A single TDCS session of the cortical motor network seemed able to restore basic cortical hypometabolism in FM patients. Further studies could clarify the long-term effect of M1 stimulation on cortical metabolism, and its relevance in pain processing and clinical features.

Interhemispheric Facilitatory Effect of High-Frequency rTMS: Perspective from Intracortical Facilitation and Inhibition.

The activity of excitatory and inhibitory neural circuits in the motor cortex can be probed and modified by transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS), noninvasively. At present, not only has a consensus regarding the interhemispheric effect of high frequency rTMS not been reached, but the attributes of these TMS-related circuits are also poorly understood. To address this question comprehensively, we integrated a single- and paired-pulse TMS evaluation with excitatory 20-Hz rTMS intervention in order to probe the interhemispheric effect on the intracortical circuits by high-frequency rTMS. In the rest state, after 20-Hz rTMS, a significant increase of single-pulse MEP and paired-pulse intracortical facilitation (ICF) in the non-stimulated hemisphere was observed with good test–retest reliability. Intracortical inhibition (measured by the cortical silent period) in the unstimulated hemisphere also increased after rTMS. No significant time–course change was observed in the sham-rTMS group. The results provide the evidence that 20-Hz rTMS induced a reliable interhemispheric facilitatory effect. Findings from the present study suggest that the glutamatergic facilitatory system and the GABAergic inhibitory system may vary synchronously.

Bihemispheric sensorimotor oscillatory network states determine cortical responses to transcranial magnetic stimulation

BackgroundBrain responses to external stimuli vary with fluctuating states of neuronal activity. Previous work has demonstrated effects of phase and power of the ongoing local sensorimotor μ-alpha-oscillation on responses to transcranial magnetic stimulation (TMS) of motor cortex (M1). However, M1 is part of a distributed network, and the effects of oscillatory activity in this network on TMS-evoked EEG responses (TEPs) have not been explored. ObjectivesTo determine the effects of oscillatory activity in the bihemispheric sensorimotor network on TEPs. Methods31 healthy subjects received single-pulse TMS of the left M1 hand area during EEG recording. Ongoing bihemispheric sensorimotor cortex oscillatory states were reconstructed from the EEG directly preceding TMS, and inferred by a data-driven method combining a multivariate autoregressive model and a Hidden Markov model. TEP amplitudes (P25, N45, P70, N100 and P180) were then compared between different bihemispheric sensorimotor cortex oscillatory states. ResultsFour bihemispheric sensorimotor cortex oscillatory states were identified, with different interhemispheric expressions of theta and alpha oscillations. High alpha-power states in the stimulated sensorimotor cortex increased P25 amplitude. Alpha power in the alpha-alpha state (stimulated - non-stimulated hemisphere) correlated in both hemispheres with N45 amplitude. Theta power in the alpha-theta state correlated in the non-stimulated hemisphere with P70 amplitude. ConclusionsBihemispheric sensorimotor cortex oscillatory states contribute to TEPs, with a relevance shift from stimulated to non-stimulated M1 from P25 over N45 to P70. This significantly extends previous findings: not only ongoing local oscillations but distributed network oscillatory states determine cortical responsiveness to external stimuli.

TMS-EEG signatures of glutamatergic neurotransmission in human cortex

Neuronal activity in the brain reflects an excitation–inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation–inhibition balance.

Effect of Different Intensities of Transcranial Direct Current Stimulation on Postural Response to External Perturbation in Patients With Parkinson’s Disease

Background Habituation of postural response to perturbations is impaired in people with Parkinson’s disease (PD) due to deficits in cortico-basal pathways. Although transcranial direct current stimulation (tDCS) modulate cortico-basal networks, it remains unclear if it can benefit postural control in PD. Objective To analyze the effect of different intensities of anodal tDCS on postural responses and prefrontal cortex (PFC) activity during the habituation to the external perturbation in patients with PD (n = 24). Methods Anodal tDCS was applied over the primary motor cortex (M1) with 1 mA, 2 mA, and sham stimulation in 3 different sessions (~2 weeks apart) during 20 minutes immediately before the postural assessment. External perturbation (7 trials) was applied by a support base posterior translation (20 cm/s and 5 cm). Primary outcome measures included lower limb electromyography and center of pressure parameters. Measures of PFC activity are reported as exploratory outcomes. Analyses of variance (Stimulation Condition × Trial) were performed. Results Habituation of perturbation was evidenced independent of the stimulation conditions. Both active stimulation intensities had shorter recovery time and a trend for lower cortical activity in the stimulated hemisphere when compared to sham condition. Shorter onset latency of the medial gastrocnemius as well as lower cortical activity in the nonstimulated hemisphere were only observed after 2 mA concerning the sham condition. Conclusions tDCS over M1 improved the postural response to external perturbation in PD, with better response observed for 2 mA compared with 1 mA. However, tDCS seems to be inefficient in modifying the habituation of perturbation.

TDCS Anodal tDCS increases bilateral corticospinal excitability irrespective of hemispheric dominance

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that utilizes weak direct currents to induce polarity-dependent modulation of corticospinal excitability. Although tDCS exerts a modulatory effect over the stimulation region, several studies have also demonstrated that distal areas of the brain connected to the region of stimulation may also be affected, as well as the contralateral hemisphere. Objective: We examined the effect of a single session of anodal tDCS on corticospinal excitability and inhibition of both the stimulated and non-stimulated hemisphere and examined the influence of these responses by the brain-derived neurotrophic factor (BDNF) polymorphism. Methods: In a randomized cross-over design, changes in corticospinal excitability and inhibition of the stimulated and non-stimulated hemispheres were analysed in 13 participants in both the dominant and non-dominant primary motor cortex (M1). Participants were exposed to 20 min of anodal and sham tDCS and also undertook a blood sample for BDNF genotyping. Results: TMS revealed a bilateral increase in corticospinal excitability irrespective of which hemisphere (dominant vs non-dominant) was stimulated (all P < 0.05). Furthermore, the induction of corticospinal excitability was influenced by the BDNF polymorphism. Conclusion: This finding shows that anodal tDCS induces bilateral effects in corticospinal excitability irrespective of hemispheric dominance. This finding provides scientists and medical practitioners with a greater understanding as to how this technique may be used as a therapeutic tool for clinical populations.

1 Hz Repetitive Transcranial Magnetic Stimulation of the Primary Motor Cortex: Impact on Excitability and Task Performance in Healthy Subjects.

Neuronavigated repetitive transcranial stimulation (rTMS) at a frequency of 1 Hz was shown to reduce excitability in underlying brain areas while increasing excitability in the opposite hemisphere. In stroke patients, this principle is used to normalize activity between the lesioned and healthy hemispheres and to facilitate rehabilitation. However, standardization is lacking in applied protocols, and there is a poor understanding of the underlying physiologic mechanisms. Furthermore, the influence of hemispheric dominance on the intervention has not been studied before. A systematic evaluation of the effects in healthy subjects would deepen the understanding of these mechanisms and offer insights into ways to improve the intervention. Twenty healthy subjects underwent five 15-minute sessions of neuronavigated rTMS or sham stimulation over their dominant or nondominant motor cortex. Dominance was assessed with the Edinburgh Handedness Inventory. Changes in both hemispheres were measured using behavioral parameters (finger tapping, grip force, and finger dexterity) and TMS measures (resting motor threshold, recruitment curve, motor area, and cortical silent period). All subjects tolerated the stimulation well. A pronounced improvement was noted in finger tapping scores over the nonstimulated hemisphere as well as a nonsignificant reduction of the cortical silent period in the stimulated hemisphere, indicating a differential effect of the rTMS on both hemispheres. Grip force remained at the baseline level in the rTMS group while decreasing in the sham group, suggesting the rTMS counterbalanced the effects of fatigue. Lastly, dominance did not influence any of the observed effects. This study shows the capability of the applied low-frequency rTMS protocol to modify excitability of underlying brain areas as well as the contralateral hemisphere. It also highlights the need for a better understanding of underlying mechanisms and the identification of predictors for responsiveness to rTMS. However, results should be interpreted with caution because of the small sample size.

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.

Transcranial direct-current stimulation (tDCS) improves detection of simple bright stimuli by amblyopic Long Evans rats in the SLAG task and produces an increase of parvoalbumin labelled cells in visual cortices

In this work visual functional improvement of amblyopic Long Evans rats treated with tDCS has been assessed using the “slow angled-descent forepaw grasping” (SLAG) test. This test is based on an innate response that does not requires any memory-learning component and has been used before for measuring visual function in rodents. The results obtained show that this procedure is useful to assess monocular but not binocular deficits, as controls and amblyopic animals showed significant differences during monocular but not during binocular assessment. On the other hand, parvoalbumin labelling was analysed in three areas of the visual cortex (V1M, V1B and V2L) before and after tDCS treatment. No changes in labelling were observed after monocular deprivation. However, tDCS treatment significantly improved vision through the amblyopic eye, and a significant increase of parvoalbumin-positive cells was observed in the three areas, both in the stimulated hemisphere but also in the non-stimulated hemisphere. This effect occurred both in control and amblyopic animals. Thus, tDCS induced changes are similar in controls and amblyopic animals, although only the last one showed a functional improvement.

ID 300 – Cortical excitability and connectivity in early RRMS using TMS-EEG

Objective Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system frequently affecting the corpus callosum, the largest interhemispheric fiber bundle, at an early stage of the disease. Here, we employed transcranial magnetic stimulation (TMS) combined with high-density 64-channel electroencephalography (EEG) to investigate cortical excitability and interhemispheric connectivity in 13 patients with early relapsing-remitting MS (RRMS) with mean EDSS 1 ± 1 compared to 16 age- and gender-matched healthy controls. Methods TMS was applied to the left and right M1 separately. Latencies and amplitudes of TMS-evoked EEG potential (TEP) components N45, N100, P180, N280 in the stimulated and non-stimulated hemisphere were analyzed using two different approaches: a cluster-based permutation analysis and an automated extraction of maximum and minimum values. Results Compared to healthy control subjects, RRMS patients did not show any significant differences in TEP latencies or amplitudes in the stimulated or non-stimulated hemisphere, neither for left nor for right M1 stimulation (all p > 0.05). Conclusion and key message We conclude that basic excitability and connectivity measures of TMS-EEG data are unaltered in early RRMS patients, which may indicate a high level of functional compensation for structural deficits in these patients, e.g. by activation of alternate routes of TEP propagation.

High-Frequency Stimulation of the Subthalamic Nucleus Counteracts Cortical Expression of Major Histocompatibility Complex Genes in a Rat Model of Parkinson’s Disease

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson’s disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

IS 32. Impaired cortical plasticity in schizophrenia

Questions Neural plasticity involves reorganization of synaptic connections and represents the brain’s capacity to reorganize its function in response to a challenge or to a stimulus. Plasticity implies changing synaptic activity and connectivity and the underlying mechanisms are long-term potentiation (LTP) and long-term depression (LTD). Methods In four studies, using excitability-enhancing anodal and excitability-diminishing cathodal transcranial direct current stimulation (tDCS) and transcranial theta-burst stimulation (TBS), we performed an in vivo assessment of glutamatedependent LTP-like and LTD-like cortical plasticity in schizophrenia patients, their relatives and healthy controls with no family history of schizophrenia. To determine the physiological basis of possible plasticity changes, different inhibitory and facilitatory networks were investigated. Furthermore, the impact of the brain-derived-neurotrophic factor on cortical plasticity was analysed. Results Multi-episode schizophrenia patients showed significantly reduced LTP-like plasticity compared to recent-onset schizophrenia patients and healthy controls. All schizophrenia patients presented abolished LTD-like plasticity and schizophrenia patients showed a dysfunctional plasticity spread (LTD) across hemispheres. First-degree relatives showed an inversed plasticity reaction compared to healthy controls and schizophrenia patients on the non-stimulated hemisphere. Conclusions The pattern of our results provides evidence for a specific plasticity deficit in schizophrenia patients which might be associated with a hyperglutamatergicstate, dysfunctional N -methyl- d -aspartate-receptors and dysfunctional intracortical inhibitory networks across hemispheres. These results indicate that the available transcranial stimulation techniques might be not optimal for the treatment of schizophrenia. New treatment tools need to be developed and the effects of the disease state, medication and the genetic background need to be taken into consideration.

P 81. Effects of motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral primary motor cortex

Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Repetitive transcranial magnetic stimulation (rTMS) is known to induce long-term potentiation (LTP) and long-term depression (LTD) like effect on the stimulated M1. Reported effects of rTMS on the contralateral non-stimultaed M1 are variable between the rTMS techniques and their mechanisms are not fully understood. Quadripulse transcranial magnetic stimulation (QPS) over M1 is known to induce LTP/LTD like plasticity in the stimulated M1. We tested whether QPS over M1 would induce plasticity on the contralateral non-stimulated M1 by measuring motor evoked potentials (MEPs). We also measured several parameters for intracortical and interhemispheric excitability changes in the contralateral M1. Subjects were twelve normal volunteers. We applied QPS over the left M1. The QPS protocol consisted of trains of 4 monophasic TMS pulses separated by inter-stimulus intervals (ISIs) of 5 ms (QPS-5) or 50 ms (QPS-50) with an inter-train interval of 5 s for 30 min. We recorded MEPs to single pulse TMS over the left or right M1 from the relaxed first dorsal interosseous muscles on both sides, before, 0 min and 30 min after QPS. We also measured the resting and active motor thresholds (RMT and AMT), short-and long-interval intracortical inhibition (SICI and LICI), intracortical facilitation (ICF), short-interval intracortical facilitation (SICF), interhemispheric inhibition (IHI), and interhemispheric facilitation (IHF) before and after QPS. After QPS-5, MEPs from the left FDI significantly increased as well as the right FDI. After QPS-50, MEPs from the left FDI did not change significantly, whereas the right FDI decreased significantly. Neither RMT nor AMT changed from the baseline after any conditions. Intracortical inhibition (SICI and LICI) and facilitation (ICF and SICF) did not change after QPS-5 or QPS-50. Both of IHI at an ISI of 10 ms and IHF at an ISI of 4 ms from the left to right hemisphere significantly increased after QPS-5 over the left M1. The QPS-5 over left M1 could also induce LTP in non-stimulated right M1. Increase in the interhemispheric connections (IHI and IHF), without any intrinsic excitability changes in the M1, suggests that the contralateral M1 excitability increment after QPS-5 is associated with the functional potentiation of transcallosal connection from the stimulated to the non-stimulated hemisphere.

The spontaneous fluctuation of the excitability of a single node modulates the internodes connectivity: A TMS‐EEG study

Brain effective connectivity can be tracked by cerebral recruitments evoked by transcranial magnetic stimulation (TMS), as measured by simultaneous electroencephalography (TMS-EEG). When TMS is targeting the primary motor area, motor evoked potentials (MEPs) can be collected from the "target" muscles. The aim of this study was to measure whether or not effective brain connectivity changes with the excitability level of the corticospinal motor pathway (CSMP) as parameterized by MEP amplitude. After averaging two subgroups of EEG-evoked responses corresponding to high and low MEP amplitudes, we calculated the individual differences between them and submitted the grand average to sLORETA algorithm obtaining localized regions of interest (RoIs). Statistical differences of RoI recruitment strength between low and high CSMP excitation was assessed in single subjects. Preceding the feedback arrival, neural recruitment for stronger CSMP activation were weaker at 6-10 ms of homotopic sensorimotor areas BA3/4/5 of the right nonstimulated hemisphere (trend), weaker at 18-25 ms of left parietal BA2/3/40, and stronger at 26-32 ms of bilateral frontal motor areas BA6/8. The proposed method enables the tracking of brain network connectivity during stimulation of one node by measuring the strength of the connected recruited node activations. Spontaneous increases of the excitation of the node originating the transmission within the hand control network gave rise to dynamic recruitment patterns with opposite behaviors, weaker in homotopic and parietal circuits, stronger in frontal ones. The effective connectivity within bilateral circuits orchestrating hand control appeared dynamically modulated in time even in resting state as probed by TMS.

Impaired Motor Cortex Responses in Non-Psychotic First-Degree Relatives of Schizophrenia Patients: A Cathodal tDCS Pilot Study

BackgroundSchizophrenia has recently been described as a disorder of impaired plasticity and dysconnectivity. Several lines of evidence suggest that alterations in glutamatergic neurotransmission underlie different symptom domains of schizophrenia. Little is known about the impact of genetic liability on cortical plasticity and connectivity in schizophrenia. ObjectiveTo compare N-methyl-d-aspartate receptor (NMDAR)-dependent cortical plasticity and connectivity in schizophrenia patients and unaffected first-degree relatives to that in healthy subjects. MethodsCortical plasticity can be induced in the motor cortex with cathodal transcranial direct current stimulation (tDCS). Animal and human research indicates that this long-term depression-like plasticity (LTD-like) is NMDAR dependent, and that these plasticity shifts can last for several hours. tDCS-induced plasticity was assessed by measuring motor-evoked potentials (MEPs) generated by applying transcranial magnetic stimulation (TMS) to both hemispheres in healthy controls, chronically ill schizophrenia patients and unaffected first-degree relatives. ResultsCompared to healthy controls, both first-degree relatives and schizophrenia patients showed abolished motor-cortical LTD-like plasticity of the stimulated hemisphere. On the non-stimulated hemisphere, plasticity was again abolished in schizophrenia patients, whereas first-degree relatives had a reversed plasticity. ConclusionsNon-psychotic and clinically unaffected first-degree relatives showed an alteration and a reversal of LTD-like cortical plasticity, indicating functional alterations of glutamatergic transmission as a result of a genetic liability for developing schizophrenia. These results provide new evidence for the association between plasticity dysregulation and functional cortical connectivity, and the importance of these networks in the pathophysiology of schizophrenia.

The Dynamic Nature of Top-Down Signals Originating from Prefrontal Cortex: A Combined fMRI–TMS Study

The prefrontal cortex (PFC) is proposed to be the source of top-down signals that can modulate extrastriate visual processing in accordance with behavioral goals, yet little direct causal evidence for this hypothesis exists. Using theta burst transcranial magnetic stimulation, we disrupted PFC function in human participants before performing a working memory task during fMRI scanning. PFC disruption decreased the tuning of extrastriate cortex responses, coinciding with decrements in working memory performance. We also found that activity in the homologous PFC region in the nonstimulated hemisphere predicted performance following disruption. Specifically, those participants with greater homologous PFC activity and greater connectivity between this region and extrastriate cortex were the most resistant to PFC disruption. These findings provide evidence for a compensatory mechanism following insults to the brain, and insight into the dynamic nature of top-down signals originating from the PFC.

Favorable and unfavorable lactation modulates the effects of electrical stimulation on brain excitability: A spreading depression study in adult rats

AimsWe investigated how different nutritional states resulting from distinct lactation conditions modulate the effects of cortical electrical stimulation (CES) on the excitability-related phenomenon known as cortical spreading depression (CSD). Main methodsWistar rats were reared in different litter sizes with 12, 6 or 3 pups, designated as malnourished (M), well-nourished (W) and overnourished (Ov), respectively. CSD was recorded for 4h on 2 cortical points of each cerebral hemisphere at baseline and after CES. CES was applied for 20min on the left cortex using a bipolar electrode placed between the CSD recording electrodes. Paired Student t test and ANOVA followed by Tukey test were used for statistical analysis (p<0.05). Key findingsThe lactation conditions significantly influenced body weight (the M and Ov groups presented the lowest and largest average weight, respectively) and modified the CSD velocities of propagation in adulthood (Ov<W<M CSD velocity). CES increased CSD velocity of propagation in the stimulated hemisphere in all groups, and in the non-stimulated hemisphere (8.66%±1.38) in the Ov group only. We observed nutritional-dependent CES effects on cortical excitability as evaluated by the different CSD velocities across the three groups (mean±sem, M (10.13%±1.70), Ov (14.65%±1.10) and W (25.70%±5.05)). SignificanceThese findings suggest valuable mechanisms of action for the brain stimulation techniques, which have gained importance because of their increasing use for the treatment of neuropsychiatric diseases. Data also suggest modulation of CES-effects by baseline excitability (as determined by the early nutritional state).

Biomarkers and neurobiology of schizophrenia

Biomarkers and neurobiology of schizophrenia

Abnormal bihemispheric responses in schizophrenia patients following cathodal transcranial direct stimulation

Post-mortem and in vivo studies provide evidence for a link between reduced plasticity and dysconnectivity in schizophrenia patients. It has been suggested that the association between plasticity and connectivity contributes to the pathophysiology and symptomatology of schizophrenia. However, little is known about the impact of glutamate-dependent long-term depression (LTD)-like cortical plasticity on inter-hemispheric connectivity in schizophrenia patients. The aim of the present study was to investigate LTD-like cortical plasticity following excitability-diminishing cathodal transcranial direct current stimulation (tDCS) of the left primary motor cortex (M1) and its effects on the non-stimulated right M1. Eighteen schizophrenia patients and 18 matched (age, gender, handedness, and smoking status) control subjects were investigated in this study. Corticospinal excitability changes following tDCS and intra-cortical inhibitory circuits were monitored with transcranial magnetic stimulation. On the stimulated hemisphere, cathodal tDCS increased resting motor thresholds (RMT) in both groups and decreased motor-evoked potential (MEP) sizes in healthy controls to a greater extent compared to schizophrenia patients. On the non-stimulated hemisphere, RMTs were increased and MEPs were decreased only in the healthy control group. Our results confirm previous findings of reduced LTD-like plasticity in schizophrenia patients and offer hypothetical and indirect in vivo evidence for an association between LTD-like cortical plasticity and inter-hemispheric connectivity in schizophrenia patients. Moreover, our findings highlight the impact of plasticity on connectivity. Dysfunctional N-methyl d-aspartate receptors or modulation of dopaminergic transmission can explain these findings. Nevertheless, the effects of antipsychotic medication still need to be considered.