21 research outputs found
Phase-amplitude coupled persistent theta and gamma oscillations in rat primary motor cortex in vitro
No full textIn vivo, theta (4-7 Hz) and gamma (30-80 Hz) neuronal network oscillations are known to coexist and display phase-amplitude coupling (PAC). However, in vitro, these oscillations have for many years been studied in isolation. Using an improved brain slice preparation technique we have, using co-application of carbachol (10 mu M) and kainic acid (150 nM), elicited simultaneous theta (6.6 +/- 0.1 Hz) and gamma (36.6 +/- 0.4 Hz) oscillations in rodent primary motor cortex (M1). Each oscillation showed greatest power in layer V. Using a variety of time series analyses we detected significant cross-frequency coupling in 74% of slice preparations. Differences were observed in the pharmacological profile of each oscillation. Thus, gamma oscillations were reduced by the GABAA receptor antagonists, gabazine (250 nM and 2 mu M), and picrotoxin (50 mu M) and augmented by AMPA receptor antagonism with SYM2206 (20 mu M). In contrast, theta oscillatory power was increased by gabazine, picrotoxin and SYM2206. GABA(B) receptor blockade with CGP55845 (5 mu M) increased both theta and gamma power, and similar effects were seen with diazepam, zolpidem, MK801 and a series of metabotropic glutamate receptor antagonists. Oscillatory activity at both frequencies was reduced by the gap junction blocker carbenoxolone (200 mu M) and by atropine (5 mu). These data show theta and gamma oscillations in layer V of rat M1 in vitro are cross-frequency coupled, and are mechanistically distinct. The development of an in vitro model of phase-amplitude coupled oscillations will facilitate further mechanistic investigation of the generation and modulation of coupled activity in mammalian cortex. (C) 2017 The Authors. Published by Elsevier Ltd
Bradykinesia is driven by cumulative beta power during continuous movement and alleviated by GABAergic modulation in Parkinson’s disease
No full textSpontaneous and “event-related” motor cortex oscillations in the beta (15–30 Hz) frequency range are well-established phenomena. However, the precise functional significance of these features is uncertain. An understanding of the specific function is of importance for the treatment of Parkinson's disease (PD), where attenuation of augmented beta throughout the motor network coincides with functional improvement. Previous research using a discrete movement task identified normalization of elevated spontaneous beta and postmovement beta rebound following GABAergic modulation. Here, we explore the effects of the gamma-aminobutyric acid type A modulator, zolpidem, on beta power during the performance of serial movement in 17 (15M, 2F; mean age, 66 ± 6.3 years) PD patients, using a repeated-measures, double-blinded, randomized, placebo-control design. Motor symptoms were monitored before and after treatment, using time-based Unified Parkinson's Disease Rating Scale measurements and beta oscillations in primary motor cortex (M1) were measured during a serial-movement task, using magnetoencephalography. We demonstrate that a cumulative increase in M1 beta power during a 10-s tapping trial is reduced following zolpidem, but not placebo, which is accompanied by an improvement in movement speed and efficacy. This work provides a clear mechanism for the generation of abnormally elevated beta power in PD and demonstrates that perimovement beta accumulation drives the slowing, and impaired initiation, of movement. These findings further indicate a role for GABAergic modulation in bradykinesia in PD, which merits further exploration as a therapeutic target
Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro
No full textBeta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation
Phase-amplitude coupled persistent theta and gamma oscillations in rat primary motor cortex in vitro
No full textIn vivo, theta (4-7 Hz) and gamma (30-80 Hz) neuronal network oscillations are known to coexist and display phase-amplitude coupling (PAC). However, in vitro, these oscillations have for many years been studied in isolation. Using an improved brain slice preparation technique we have, using co-application of carbachol (10 μM) and kainic acid (150 nM), elicited simultaneous theta (6.6 ± 0.1 Hz) and gamma (36.6 ± 0.4 Hz) oscillations in rodent primary motor cortex (M1). Each oscillation showed greatest power in layer V. Using a variety of time series analyses we detected significant cross-frequency coupling 74% of slice preparations. Differences were observed in the pharmacological profile of each oscillation. Thus, gamma oscillations were reduced by the GABAA receptor antagonists, gabazine (250 nM and 2 μM), and picrotoxin (50 μM) and augmented by AMPA receptor antagonism with SYM2206 (20 μM). In contrast, theta oscillatory power was increased by gabazine, picrotoxin and SYM2206. GABAB receptor blockade with CGP55845 (5 μM) increased both theta and gamma power, and similar effects were seen with diazepam, zolpidem, MK801 and a series of metabotropic glutamate receptor antagonists. Oscillatory activity at both frequencies was reduced by the gap junction blocker carbenoxolone (200 μM) and by atropine (5 μM). These data show theta and gamma oscillations in layer V of rat M1 in vitro are cross-frequency coupled, and are mechanistically distinct. The development of an in vitro model of phase-amplitude coupled oscillations will facilitate further mechanistic investigation of the generation and modulation of coupled activity in mammalian cortex
Characteristics of beta activity in local field potentials (LFPs).
No full text<p>Layer II and V LFPs show significant power in the beta frequency range, which is both correlated and significantly coherent between layers II and V. (A), sample of filtered recording showing LFPs acquired concurrently in layer II (upper record) and layer V (lower record). (B), power spectra derived from these LFPs, plotted on log scales as power spectral densities (PSD), showing peaks in beta (20–30 Hz) range. (C) and (D), power spectra of same LFPs from layer II and layer V respectively, on linear scales, showing 99% significance levels above red lines. Significant peaks are present at 25.7 Hz (layer II), and at both 26.6 and 51.9 Hz (layer V), with no single clear peak shown in range 40–100 Hz in layer II, although significant power is evident. (E), strong cross-correlation of LFPs from layers II and V, with period of around 34 ms. (F), coherence between LFPs in layer V and layer II (in same recordings as (A) is significant at 99% confidence level (above red line) at 10.3 and 50.3 Hz, but most markedly at 27.6 Hz.</p
Basic intracellular properties of recorded cells used in this study.
No full text<p><sup>1</sup> 4 cells were quiescent; <sup>2</sup> at ½ maximal amplitude; <sup>3</sup> in range −55 to −75 mV.</p
Layer V pyramidal cells action potentials are coherent with and phase-locked to LFPs.
No full text<p>(A) membrane potential (Vm) recording (without DC current injection), with spontaneous action potentials (spikes), together with concurrent (unfiltered) records of LFPs. (B), left panels: Power spectral densities in LFPs are significant (99% above red lines) in beta range, but for Vm are close to spontaneous spike firing rate. Right panels: coherence between Vm and layers V and II LFP is seen in beta range, and harmonics thereof (same recordings as A). (C), upper panel: spike-triggered averages of LFPs from layer V (red) and II (blue), time-locked to each of 84 spikes occurring over a 10 s period (at t = 0 on x-axis). Spikes precede by 2–3 ms the trough, and peak, of the layer V and II oscillations respectively, both of which display a period of around 40 ms. Taken from same cell as in A and B. Lower panel: pooled, normalised, layer V LFP spike-triggered average data (mean ± SEM) from all the 10 recordings that showed significant coherence in the 15–40 Hz range between layer V LFP and Vm (during spontaneous firing). The layer V LFP peak follows the spike by approximately 20 ms. (D), upper panels: Records of (Vm) recorded at rest, during spontaneous spike firing, and of layer V and II LFPs, in absence (left) and presence (right) of bicuculline (10 µM). While spikes persist in bicuculline, LFP oscillations are abolished. Lower panels: significant beta range coherence between Vm and both layer V and II LFP (left) is abolished in bicuculline (right). Different preparation from panels A–C. (E), data pooled from all recordings showing the distribution of frequencies at which significant coherence between LFPs in layer II and layer V, and spikes, was detected, grouped into 3 frequency bands (mean ± SEM in red, n in parentheses).</p
Properties of a layer V pyramidal cell, demonstrated with sharp microelectrode intracellular recording.
No full text<p>(A), recording of resting membrane potential, showing spontaneous action potential firing at 18.1 Hz. Right panel: a single action potential on an expanded time scale, with dashed cursor lines indicating method of measuring amplitude (between top and bottom horizontal cursors: 65.3 mV) and duration at ½ maximal amplitude (between vertical cursors: 1.10 ms). (B), superimposed records of membrane potential showing response to successive 200 ms hyperpolarizing pulses of current (not shown) injected in multiples of 0.2 nA from baseline of zero (ie. resting potential). (C), voltage-current plot derived from a series of current pulses injected in multiples of 0.1 nA into the same cell [including those in (B)] in which steady-state voltage attained near end of current pulse [dashed vertical line in (B)] is plotted. Slope of line (best fit in range −55 to −75 mV) yields input resistance value of 45 MΩ. All records from the same cell.</p
Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons
No full textTonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15–30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states
IPSPs in layer V cells are strongly coherent with LFPs in the beta range.
No full text<p>(A) Concurrent LFPs from layers V and II, and intracellularly recorded membrane potential (Vm) from a cell in layer V. Oscillations and IPSPs (at −80 mV, optimised for IPSPs) are blocked following application of GABA<sub>A</sub> receptor antagonist bicuculline (right panel). (B) Power spectral densities (PSD) of LFPs from layers V and II, and of Vm (with IPSPs), showing 99% significance levels (above red lines) at beta frequencies, and harmonics thereof, which (right panels) are blocked by bicuculline. Vertical dashed lines indicate 27 Hz for reference. Same recordings as (A). (C), upper panel: cross-correlograms of LFPs from layers II (blue) and V (red) with Vm from same recordings as in (A) and (B). Lower panel: normalised, cross-correlated data (means+SEM) between Vm (displaying IPSPs) and LFPs in layer V (red) and layer II (blue) pooled from all 20 recordings showing significant IPSP-LFP coherence in 15–40 Hz range. The IPSP leads layer V peak (red dashed line) by 7.2 ms and layer II peak (blue dashed line) by 20.5 ms. (D) Left column: coherence between each of layer II and layer V LFP (top row), layer II LFP and IPSPs (middle row), and layer V LFP and IPSPs (bottom row) in each case demonstrates single significant (>99%) peaks at beta frequencies, and harmonics thereof, which is abolished by bicuculline (right panels). Same recordings as A, B and C. (E) and (F), data pooled from all recordings within 3 frequency ranges (demarked by vertical dashed lines, with mean ± SEM in red, n in parentheses) showing (E) the distribution of the single largest significant (>99%) power spectrum peaks for Vm (optimised for IPSPs), and (F) peak frequencies of coherence between LII, LV, and Vm (IPSPs).</p
