WHICH BIOMARKER
FOR MY RESEARCH ?

EEG Biomarkers provide objective measures
of Brain [dys]function. At the source.

Modified electrical activity in neuronal networks is symptomatic of a wide range of CNS disorders.

Local Field Potentials (LFP) are recorded in vivo by EEG, in the brain of freely-moving, translational models. These oscillations offer a direct window on neuronal networks activity.

Disease-specific EEG signatures can be used as surrogate Biomarkers to assess your compounds effects in vivo, longitudinally.

Unique on the market, our EEG Biomarker approach delivers smooth human-rodent translation, high reproducibility levels and robust endpoints, particularly well-suited to evaluate your compounds effects with no bias.

The Term of the Month, by SynapCell

Every month, we pick and explain one of the EEG Biomarkers we have developed for preclinical research.

Your EEG biomarker of interest is not yet explained above? No worries, new content every month here, so stay tuned !

What is Phase-amplitude coupling (PAC)?

Phase Amplitude Coupling reflects the interactions between oscillations in different bands and helps understand brain function. Involved in sensory integration, PAC is observed in rodents, monkeys, and in humans. The theta-gamma PAC could be a potential new biomarker of Parkinson's Disease.

Phase Amplitude Coupling

Exacerbated phase-amplitude coupling between beta-phase (13-30 Hz) and gamma-amplitude (50-200 Hz) has been characterized in the motor cortex of PD patients.

A strong coupling between the phase of theta (4-6Hz) and the amplitude of high gamma (90-160Hz) in the ipsilateral motor cortex of 6-OHDA lesioned rats.

Phase Amplitude Coupling

In addition, anti-parkinsonian drugs like L-Dopa, apomorphine or SKF-38393-2, significantly suppressed this theta-gamma PAC.

This theta-gamma PAC signature in an animal model of PD can be used as a new translational biomarker, thus providing a stable, quantifiable, reliable and objective endpoint for the development of new therapies against PD.

Parkinson's Disease
View communication at AD/PD2019
PAC was March Term of the Month

What are Event (evoked) related Potentials (ERP)?

In rodents, EEG responses evoked by auditory stimulation can be recorded in various brain areas and underlie the integration and processing of sensory information which are altered in a large number of neurological and psychiatric disorders.

Widely adopted in patients, we can distinguish two main types of auditory evoked responses:

the auditory evoked related potentials (AERP)
and the auditory steady state response (ASSR)

AERPs are composed of successive positive and negative deflections, which differ from their latencies and amplitudes and are well conserved throughout the evolution.

These features make AERPs readouts easily translatable from preclinical models of psychiatric disorders to human patients, and enable the objective measure of the impact of drug candidates on information processing by the brain in healthy or relevant models of psychiatric or cognitive disorders (transgenic models, pharmaco-induced models or surgical models).

AERP-by-SynapCell-In-vivo-efficacy-Testing-on-CNS-disorders

ERP protocols can be very useful to test a novel mecanism of action of a compound, measure how the brain integrates and processes new information and get the phenotype of an experimental animal model of psychiatric disorder (Ketamine modelisation and NMDA hypofunction in schizophrenia for example).

What are SWD?

Absence epilepsy is a particular form of epileptic syndrome where patients show generalized non-convulsive seizures characterized by a brief unresponsiveness to environmental stimuli and cessation of activity. In human, typical absence seizures are associated with bilateral, synchronous and regular spike and wave discharges (SWD) (Loiseau et al., 1995). These epileptiform patterns are characterized by the repetitive occurrence of a Spike followed by Slow Wave.

This type of epilepsy presents a specific pharmacology different from the one observed in other types of epilepsies. Therefore, careful evaluation of new antiepileptic drugs in development is mandatory regarding a possible aggravation of SWD in idiopathic generalized epilepsies (Manning et al., 2003; Genton, 2000) and particularly absence epilepsy.

The genetic absence epilepsy rat from Strasbourg (GAERS) is a selectively inbred strain of Wistar rats displaying spontaneous SWD. For the past thirty years, the GAERS has become a reference model for absence epilepsy, since these rats were shown to present behavioral, electrophysiological, and pharmacological features of absence seizures (Depaulis et al., 2016).
Cortical EEG recording is characterized by SWD lasting 18-25 sec, with a recurrence of 45-60 seizures per hour. SWD start and end abruptly and are associated with a behavioral arrest lasting the time of the discharge (Vergnes et al., 1982).

As in human patients, SWD in GAERS are suppressed by antiepileptic drugs (AED) such as valproate (Dedeurwaerdere et al., 2011), ethosuximide (Nehlig et al., 1993) and levetiracetam (Gower et al., 1995), whereas other AEDs have no efficacy (lacosamide, Higgins et al., 2010) or can even aggravate SWD, particularly carbamazepine (Wallengren et al., 2005), phenytoin (Gurbanova et al., 2006), and high doses (>200mg/kg) of pregabalin (Vartanian et al., 2006).

The use of SWD as a biomarker for absence epilepsy therefore offers very high predictivity level for identifying anti-absence as well as pro-epileptic effect for AED in development or other compounds acting on the CNS (Klitgaard et al., 2002; van Luijtelaar et al., 2002).

Generalized Absence Epilepsy

The GAERS on Wikipedia
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What are HPD?

Mesio-Temporal Lobe Epilepsy represents a major challenge in the clinical management of seizures.

This form of epilepsy is often associated with severe cognitive and emotional impairments, and affects about 10% of the total epileptic population. In addition, MTLE becomes generally resistant to most pharmacological treatments (Engel et al., 1997).

SynapCell has developed an animal model of MTLE in which, unlike most other models, dispersion of the dentate gyrus is observed (Bouilleret et al., 1999 and Riban et al., 2002). In this model, unilateral injection of a small dose of kainate (1 nmole) in the dorsal hippocampus of mice results in neuronal losses in CA1, CA3 areas and hilus as well as mossy fiber sprouting, in addition to an important dispersion and increase of granule cells of the dentate gyrus (Suzuki et al., 1995 and Mitsuya et al., 2009).

More importantly, this model is resistant to most classical antiepileptic drugs: valproate, carbamazepine and lamotrigine can suppress the hippocampal discharges upon acute treatment only at high doses and with side effects (Riban et al., 2002; Duveau et al., 2016). We have shown that HPD are dose-dependently suppressed by acute administration of diazepam. However, recently developed AEDs, such as pregabalin, levetiracetam or vigabatrin were shown to be active on this model with no side effects (Duveau et al., 2016).

HPD-MTLE-Pharmacology-synapcell-In-vivo-efficacy-Testing-on-CNS-disorders

Focal Epilepsy

Epileptic disorders

View Abstract
Video on YouTube

What is ASSR?

Sensory information Integration and processing by the brain are altered in several neurological and psychiatric disorders, especially in schizophrenia.
This integration of sensory information can be monitored using EEG in the auditory cortex. Several experimental protocols are commonly used in the clinic on human patients.
That includes the use of Auditory Event-Related Potential (AERP) protocols, which consists in stimulating the auditory cortex with one single short noise (a click) then recording the resulting cortical response, characterized by typical positive and negative deflections, well described in the clinical litterature.

Another type of auditory stimulation protocol is the Auditory Steady-State Response (ASSR).
ASSRs consist in cortical electrophysiological oscillations entrained to the frequency and phase of a periodic auditory stimulus presented at a rhythm in the gamma range (that is, 30-80Hz).
ASSR protocol consists in stimulating the auditory cortex by a train of clicks (usually for 0.5 to 2 s) with a fixed inter-click interval (Brenner et al., 2009). After an initial response lasting ~250 ms, the train rapidly entrains the cortical activity to the stimulation frequency and phase of the stimulus.

ASSRs are believed to reflect the interplay between cortical pyramidal neurons and parvalbuminergic interneurons. Consistent with the theory of imbalance between cortical excitation and inhibition in schizophrenia, patients show reduced power and phase locking, to stimulations presented at 40Hz.

From the steady-state oscillation evoked by the ASSR stimulus, an entrainment power can be extracted, usually measured at the stimulation frequency (± 5 Hz) where the entrainment peaks. Two different calculations can be applied. The total power measures the total EEG power comprised in the frequency band. The evoked power measures the power of the activity that is phase-locked with the stimulation. Another calculation compares the inter-trial coherence (ITC), and was developed more recently to evaluate the phase-locking of the signal (Delorme and Makeig, 2004).

In particular, modulations of the ASSR has been studied in schizophrenia, in which auditory hallucinations and delusions is a diagnostic criterion. ASSR responses at 40 Hz have been shown to be reduced in power and phase-locking in schizophrenic patients (Kwon et al., 1999; O’Donnel et al., 2013; Sun et al., 2018).

Additionally, multiple neurotransmitter receptors and other molecules are known to impact auditory information processing, allowing these measurements to be used as target engagement biomarkers, i.e. to assess whether experimental compounds are interacting with their target molecule.

Our paradigm reproduces the clinical protocol by recording the EEG response to a train of clicks in the parietal auditory cortex and in the frontal associative cortex. Recording at these two brain levels allows evaluating the processing of auditory information at two different stages, which enables to evaluate the effect of drug candidates in a translational biomarker equivalent to a clinical protocol.

What is BetaPark?

BetaPark is a translational EEG biomarker recorded in the motor cortex of both PD patients and animal models of prodromal and late-onset PD. Suppressed by dopaminergic drugs, BetaPark is used to quantify the efficacy of therapies against PD.

Breaking it down:

Motor symptoms observed in Parkinson's Disease result from a dysfunction of the cortico-basal ganglia circuits mainly due to the progressive depletion of dopaminergic neurons in the substantia nigra pars compacta.

Accumulative evidences have demonstrated the presence of aberrant hypersynchronization of beta frequency oscillatory activity in these circuits in both parkinsonian patients (Little and Brown, 2014) and experimental animal models of the disease.

These beta activities have been correlated with symptoms such as hypokinesia and rigidity (Hammond et al., 2007, and Little et al., 2012). Treatments with dopaminergic drugs and deep brain stimulation reduce and even transiently suppress these pathological oscillations and are known to improve the motor symptoms (Hammond et al., 2007).

Pogosyan et al. (2009) also demonstrated the causality between any physiological oscillatory brain activity and concurrent motor behavior in the healthy human and that boosting cortical activity at beta frequency was slowing movement in human. This work helps explain how the exaggerated beta activity found in Parkinson's disease can lead to motor slowing in this neurodegenerative disorder.

Animal models of PD such as the MPTP non-human primate (Connolly et al., 2015), the unilateral 6-OHDA-lesioned rat (mimics PD late stage), or the bilateral AAV-alpha-synuclein (α-Syn) rat model show a prominent cortical beta activity that is significantly lowered by dopaminergic drugs, making them clinically-relevant for the evaluation of anti-PD therapies.

BetaPark is a prefect biomarker for the investigation of the two main phases of the disease: the prodromal and the symptomatic phase.

First, BetaPark allows to measure the efficacy of neuroprotective agents over several weeks in freely moving AAV-alpha-synuclein (α-Syn) rat.
Then, BetaPark precision allows for a range of accurate pharmacodynamic studies able to deliver decision-making information with the unilateral 6-OHDA-lesioned rat.

Dopaminergic agonists transiently silence BetaPark.

Pharmacosensitive and stable over time, BetaPark is dose-dependently lowered by the dopamine replacement therapy L-DOPA. The higher the L-DOPA dose, the more intense and longer effect in lowering BetaPark.

BetaPark is exclusively identified by SynapCell's state-of-the-art EEG methodologies in preclinical and clinically-relevant models of PD: in the 6-OHDA rat and in the AAV-alpha-synuclein (α-Syn) rat (undisclosed ongoing collaboration - data not shown)

BetaPark represents a predictive, reliable, objective and translational biomarker of early and late phases of PD.

BetaPark therefore presents all the features that makes it a surrogate biomarker for the identification of new treatments against PD or the validation of disease modifying experimental therapeutics.

At Synapcell, we are proud to propose a full range of possibilities to address all stages of Parkinson's disease, with a level of predictivity that's unique on the market.

Head to our Parkinson's Page for a deeper look on BetaPark, L-DOPA induced GammaPark* and contact us to dig into the data!

* L-DOPA induced GammaPark :

In Parkinson's disease, motor dysfunctions are thought to be related to an imbalance between antikinetic beta band (13-30 Hz) rhythms and prokinetic gamma band (60-90 Hz) rhythms in the motor network. Chronic treatment with L-DOPA suppresses antikinetic beta band rhythms (BetaPark) while promoting cortical oscillations in the gamma frequency band (GammaPark), that correlate to L-DOPA induced dyskinesia. GammaPark is a prefect biomarker for the investigation of therapeutical strategies against Dyskinesia.

Learn more about oscillatory activities in Essential Tremor

GammaPark is a translational EEG Biomarker for L-DOPA induced Dyskinesia, in a Parkinson's context.

Dopamine agonists lower BetaPark and increase GammaPark expression at the same time.

Anti-PD strategies with EEG aim at lowering BetaPark (Parkinsonism signature), while silencing GammaPark, after L-DOPA priming.

Discover GammaPark and the data

What is the ET band?

The Harmaline mouse model is reported to be one of the most relevant to modelize Essential Tremor.

A specific oscillatory frequency can be found in our harmaline mouse (30-55 Hz).
This band (ET Band) is lowered by today's treatments for Human patients and can be reversed by propranolol.

Check the ET page for more!

Coming soon!