Ketamine Administration During the Second Postnatal Week Alters Synaptic Properties of Fast-Spiking Interneurons in the Medial Prefrontal Cortex of Adult Mice.

The N-methyl-D-aspartic acid (NMDA)-hypofunction theory of schizophrenia suggests that schizophrenia is associated with a loss of NMDA receptors, specifically on corticolimbic parvalbumin (PV)-expressing GABAergic interneurons, leading to disinhibition of pyramidal cells and cortical desynchronization. However, the presumed changes in glutamatergic inputs onto PV interneurons have not been tested directly. We treated mice with the NMDAR antagonist ketamine during the second postnatal week and investigated persistent cellular changes in the adult medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings and immunohistochemistry. Parvalbumin expression in the mPFC was reduced in ketamine-treated (KET) mice, and γ-aminobutyric acid release onto pyramidal cells was reduced in layers 2/3, but not layer 5. Consistent with pyramidal cell disinhibition the frequency of spontaneous glutamatergic inputs onto PV cells was also increased in KET mice. Furthermore, developmental ketamine treatment resulted in an increased NMDA:AMPA ratio in evoked synaptic currents and larger amplitudes of spontaneous NMDAR currents, indicating a homeostatic upregulation of NMDARs in PV interneurons. This upregulation was specific to NR2B subunits, without concomitant alterations in currents through NR2A subunits. These changes altered synaptic integration at PV cells during trains of excitatory postsynaptic potentials. These changes likely impact synaptic coincidence detection and impair cortical network function in the NMDAR antagonism model of schizophrenia.

Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans. In Experiment 1, patterned repetitive TMS was applied to left M1, consisting of 6 trains (intertrain interval, 8 s) of 4 doublets (interpulse interval equal to individual peak I-wave facilitation, 1.3-1.5 ms) spaced by the individual peak LCD (interdoublet interval (IDI), 200-250 ms). This intervention (total of 48 pulses applied over ∼45 s) increased motor-evoked potential amplitude, a marker of corticospinal excitability, in a right hand muscle by 147% ± 4%. Control experiments showed that IDIs shorter or longer than LCD did not result in LTP-like plasticity. Experiment 2 indicated topographic specificity to the M1 hand region stimulated by TMS and duration of the LTP-like plasticity of 60 min. In conclusion, GABA(B)ergic LCD offers a powerful new approach for augmenting LTP-like plasticity induction in human cortex. We refer to this protocol as disinhibition stimulation (DIS).

Changes of the Sensory Abnormalities and Cortical Excitability in Patients with Complex Regional Pain Syndrome of the Upper Extremity After 6 Months of Multimodal Treatment.

Objective: The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-term multimodal treatment are lacking. Methods: We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n = 19). Treatment response at follow-up was defined as pain relief > 30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation. Results: At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n = 17, P < 0.05), whereas there was no improvement in non-responders (n = 7). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r = 0.49, P < 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression. Conclusion: Thus, the persistence of blunt hyperalgesia seems to be associated with impaired paired-pulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup.

Temporal and spatial characteristics of post-silent period electromyographic bursting in low back muscles: comparison between persons with and without low back pain.

Purpose/aim: Recently, a novel measure of cortical disinhibition was identified using transcranial magnetic stimulation (TMS). This measure, described as post-silent period electromyographic (EMG) bursting, may inform on the corticomotor control of movement in health and disease; however, it has not been investigated for muscles outside the hand or in musculoskeletal conditions. Thus, the aim of this study was to investigate the temporal and spatial characteristics of "EMG bursting" in individuals with and without low back pain (LBP). MATERIALS AND METHODS: TMS was used to map the motor cortical representation of paraspinal muscles in 11 individuals with LBP and 11 pain-free controls. The latency, duration and magnitude of bursting, number of active burst sites, map volume and coordinates of the burst "hotspot" were compared between the groups. RESULTS: In pain-free controls, the latency, duration and magnitude of bursts were similar to the hand; however, bursts occurred earlier and were of smaller magnitude in LBP. Bursting was widespread throughout the cortical representation in both groups; however, there was a trend towards smaller mean EMG burst and map volume in LBP. CONCLUSIONS: We confirm the presence of EMG bursting in back muscles and provide a description of the spatial profile of this mechanism. Our observations in LBP suggest that cortical disinhibition may be altered in this condition.

Low test-retest reliability of a protocol for assessing somatosensory cortex excitability generated from sensory nerves of the lower back.

In people with chronic low back pain (CLBP), maladaptive structural and functional changes on a cortical level have been identified. On a functional level, somatosensory cortical excitability has been shown to be reduced in chronic pain conditions, resulting in cortical disinhibition. The occurrence of structural and/or functional maladaptive cortical changes in people with CLBP could play a role in maintaining the pain. There is currently no measurement protocol for cortical excitability that employs stimulation directly to the lower back. We developed a protocol for the measurement of single pulse somatosensory evoked potential (SEP) waveforms and paired-pulse behavior (PPB) generated from sensory nerves of the lower back and quantified its test-retest reliability in a sample of 30 healthy individuals to gain insights into the normal variability of cortical responses, which could then be compared to results from people with CLBP. We investigated cortical excitability by measuring SEPs and PPB. PPB was defined as the ratio of the amplitude of the second cortical response (A2s) divided by the first cortical response (A1). A2s was determined by subtracting the response to single-pulse stimuli from the paired pulse stimuli response to account for linear superposition effects. The test-retest reliability of the protocol was very poor with no evidence of systematic bias but a high amount of random variability between sessions. There was no significant difference in the right side PPB for session 1 (Mean ratio A2s/A1 = 0.66, SD = 0.54) and session 2 (Mean ratio A2s/A1 = 0.94, SD = 1.56); mean session difference [(95% CI) = -0.44 (-1.23 to 0.34); t (22) = -1.17, p = 0.26]. The ICC3.1 (absolute agreement) for the outlier-removed right side PPB were 0.19 (95% CI: -0.84 to 0.66) and 0.43 for left side PPB (95% CI: -0.37 to 0.76). This finding potentially has wider implications for PPB protocols. If these findings were replicated in other groups and other nerves, it would question the validity of this measure more generally. However, these findings are restricted to healthy people and sensory nerves of the lower back and may not be generalizable.

Cortical excitability in epilepsy and the impact of antiepileptic drugs: transcranial magnetic stimulation applications.

INTRODUCTION: Epileptic conditions are characterized by impaired cortical excitation/inhibition balance and interneuronal disinhibition. Transcranial magnetic stimulation (TMS) is a neurophysiological method that assesses brain excitation/inhibition. AREA COVERED: This review was written after a detailed search in PubMed, EMBASE, ISI web of science, SciELO, Scopus, and Cochrane Controlled Trials databases from 1990 to 2020. It summarizes TMS applications for diagnostic and therapeutic purposes in epilepsy. TMS studies help to distinguish different epilepsy conditions and explore the antiepileptic drugs' (AEDs') effects on neuronal microcircuits and plasticity mechanisms. Repetitive TMS studies showed that low-frequency rTMS (0.33-1 Hz) can reduce seizures' frequency in refractory epilepsy or pause ongoing seizures; however, there is no current approval for its use in such patients as adjunctive treatment to AEDs. EXPERT OPINION: There are variable and conflicting TMS results which reflect the distinct pathogenic mechanisms of each epilepsy condition, the dynamic epileptogenic process over the long disease course resulting in the development of recurrent spontaneous seizures and/or progression of epilepsy after it is established, and the differential effect of AEDs on cortical excitability. Future epilepsy research should focus on combined TMS/functional connectivity studies that explore the complex cortical excitability circuits and networks using different TMS parameters and techniques.

Late cortical disinhibition in relaxed versus active hand muscles.

Recent research suggests that long-interval intracortical inhibition (LICI) is followed by a transitory period of late cortical disinhibition (LCD) that can even lead to a net increase in cortical excitability. The relationship between LICI/LCD and voluntary drive remains poorly understood. Our study aims at investigating the influence of index abduction on LICI and LCD in an actively engaged muscle and a neighboring muscle, while varying the intensity of the conditioning stimulus (CS). Motor-evoked potentials (MEPs) were recorded from the first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles in 13 subjects. Paired-pulses were delivered with 10 different interstimulus intervals (ranging from 60 to 290 ms). Whatever the condition (relaxed or active FDI), the test stimulus was set to evoke an MEP of 1mV. The time course of conditioned MEP amplitude was compared for relaxed and active conditions when the CS intensity was set to (i) 130% of the rest motor threshold (RMT) or (ii) to evoke the same size of MEP under both conditions. LICI lasted longer (i.e. disinhibition occurred later) at rest than during abduction when evoked either by similar or matched conditioning stimuli. No post-LICI facilitation was observed at rest - even when the CS intensity was set to 160% RMT. In contrast, long-interval intracortical facilitation (LICF) was observed in the quiescent ADM when FDI was active. LICF may then be associated with voluntary activity albeit with lack of topographic specificity.

Effects of Repetitive High Frequency Motor Cortex Transcranial Magnetic Stimulation and Cortical Disinhibition in Diabetic Patients with Neuropathic Pain: A Case Control Study

OBJECTIVE: To investigate the cortical disinhibition in diabetic patients with neuropathic pain and without pain. In addition, we assessed the cortical disinhibition and pain relief after repetitive transcranial magnetic stimulation (rTMS).METHOD: We recruited diabetic patients with neuropathic pain (n = 15) and without pain (n = 15). We compared the TMS parameters such as motor evoked potential (MEP) amplitude, cortical silent period (CSP), intracortical inhibition (ICI %) and intracortical facilitation (ICF %) between two groups. Moreover, we evaluated the changes of pain and TMS parameters after five consecutive high frequency (10 Hz) rTMS sessions in diabetic patients with neuropathic pain. The neuropathic pain intensity (visual analog scale) and TMS parameters were assessed on pre-rTMS, post-rTMS 1day, and post-rTMS 5 day.RESULTS: The comparison of the CSP, ICI % revealed significant differences between two groups (p<0.01). After rTMS sessions, the decrease in pain intensity across the three time points revealed a pattern of significant differences (p<0.01). The change of CSP and ICI % across the three test points revealed a pattern of significant differences (p<0.01). The ICI % revealed immediate increase after first rTMS application and significant increase after five rTMS application (p<0.01) in diabetic patients with neuropathic pain. The MEP amplitude and ICF % did not reveal any significant changes.CONCLUSION: Our findings demonstrate that cortical inhibition was decreased in diabetic patients with neuropathic pain compared with patients without pain. Furthermore, we also identified that five daily rTMS sessions restored the defective intracortical inhibition which related to improvement of neuropathic pain in diabetic patients.

Age-related changes across the primary and secondary somatosensory areas: an analysis of neuromagnetic oscillatory activities.

OBJECTIVE: Age-related changes are well documented in the primary somatosensory cortex (SI). Based on previous somatosensory evoked potential studies, the amplitude of N20 typically increases with age probably due to cortical disinhibition. However, less is known about age-related change in the secondary somatosensory cortex (SII). The current study quantified age-related changes across SI and SII mainly based on oscillatory activity indices measured with magnetoencephalography. METHODS: We recorded somatosensory evoked magnetic fields (SEFs) to right median nerve stimulation in healthy young and old subjects and assessed major SEF components. Then, we evaluated the phase-locking factor (PLF) for local field synchrony on neural oscillations and the weighted phase-lag index (wPLI) for cortico-cortical synchrony between SI and SII. RESULTS: PLF was significantly increased in SI along with the increased amplitude of N20m in the old subjects. PLF was also increased in SII associated with a shortened peak latency of SEFs. wPLI analysis revealed the increased coherent activity between SI and SII. CONCLUSIONS: Our results suggest that the functional coupling between SI and SII is influenced by the cortical disinhibition due to normal aging. SIGNIFICANCE: We provide the first electrophysiological evidence for age-related changes in oscillatory neural activities across the somatosensory areas.

Cognition-emotion dysinteraction in schizophrenia.

Evolving theories of schizophrenia emphasize a "disconnection" in distributed fronto-striatal-limbic neural systems, which may give rise to breakdowns in cognition and emotional function. We discuss these diverse domains of function from the perspective of disrupted neural circuits involved in "cold" cognitive vs. "hot" affective operations and the interplay between these processes. We focus on three research areas that highlight cognition-emotion dysinteractions in schizophrenia: First, we discuss the role of cognitive deficits in the "maintenance" of emotional information. We review recent evidence suggesting that motivational abnormalities in schizophrenia may in part arise due to a disrupted ability to "maintain" affective information over time. Here, dysfunction in a prototypical "cold" cognitive operation may result in "affective" deficits in schizophrenia. Second, we discuss abnormalities in the detection and ascription of salience, manifest as excessive processing of non-emotional stimuli and inappropriate distractibility. We review emerging evidence suggesting deficits in some, but not other, specific emotional processes in schizophrenia - namely an intact ability to perceive emotion "in-the-moment" but poor prospective valuation of stimuli and heightened reactivity to stimuli that ought to be filtered. Third, we discuss abnormalities in learning mechanisms that may give rise to delusions, the fixed, false, and often emotionally charged beliefs that accompany psychosis. We highlight the role of affect in aberrant belief formation, mostly ignored by current theoretical models. Together, we attempt to provide a consilient overview for how breakdowns in neural systems underlying affect and cognition in psychosis interact across symptom domains. We conclude with a brief treatment of the neurobiology of schizophrenia and the need to close our explanatory gap between cellular-level hypotheses and complex behavioral symptoms observed in this illness.