Bradykinesia Is Driven by Cumulative Beta Power During Continuous Movement and Alleviated by Gabaergic Modulation in Parkinson's Disease

Spontaneous 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.Peer reviewe

Phase-amplitude coupled persistent theta and gamma oscillations in rat primary motor cortex in vitro

In 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

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta 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

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Layer V pyramidal cells action potentials are coherent with and phase-locked to LFPs.

<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

Basic intracellular properties of recorded cells used in this study.

<p>¹ 4 cells were quiescent; ² at ½ maximal amplitude; ³ in range −55 to −75 mV.</p

Properties of a layer V pyramidal cell, demonstrated with sharp microelectrode intracellular recording.

<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

Characteristics of beta activity in local field potentials (LFPs).

<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

IPSPs in layer V cells are strongly coherent with LFPs in the beta range.

<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_A 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