Pascale Quilichini

In vivo recordings of brain activity using organic transistors

In vivo electrophysiological recordings of neuronal circuits are necessary for diagnostic purposes and for brain-machine interfaces. Organic electronic devices constitute a promising candidate because of their mechanical flexibility and biocompatibility. Here we demonstrate the engineering of an organic electrochemical transistor embedded in an ultrathin organic film designed to record electrophysiological signals on the surface of the brain. The device, tested in vivo on epileptiform discharges, displayed superior signal-to-noise ratio due to local amplification compared with surface electrodes. The organic transistor was able to record on the surface low-amplitude brain activities, which were poorly resolved with surface electrodes. This study introduces a new class of biocompatible, highly flexible devices for recording brain activity with superior signal-to-noise ratio that hold great promise for medical applications.

Highly Conformable Conducting Polymer Electrodes for In Vivo Recordings

Electronic devices that interface with living tissue have become a necessity in clinics to improve diagnosis and treatments. Devices such as cardiac pacemakers and cochlear implants stimulate and monitor electrically active cells, restoring lost function and improving quality of life. On a more fundamental level, most breakthroughs in our understanding of the basic mechanisms of information processing in the brain have been obtained by means of recordings from implantable electrodes. [ 1–3 ] Materials science is playing a pivotal role in this fi eld. For example, state-of-the-art implantable electrodes are microfabricated devices that contain high-density arrays of metal sites on a silicon shank (silicon probes). [ 4 ] Still, as neuroscience continues to advance and more options for electrical intervention become a reality for patients (ocular implants, deep-brain stimulation for epilepsy and Parkinson’s disease), [ 5 ] there is a tremendous need for developing advanced materials solutions for the biotic/abiotic interface. One such example is the necessity to develop electrodes that can conform to the curvilinear shapes of organs (e.g., the surface of the brain or its sulci) and form high-quality electrical contacts. Such surface electrodes are needed for electrocorticography (ECoG), which is increasingly used for functional mapping of cognitive processes before certain types of brain surgery (e.g., tumors) or for diagnosis purposes (e.g., epilepsy). [ 6 ] Placed on the somatosensory cortex, surface electrode arrays are also being used in brain-machine interfaces, an assistive technology for people with severe motor disabilities. [ 7 ] In contrary to silicon probes that penetrate the brain and cause tissue damage, these arrays are placed on the surface of the brain and are hence less invasive.

Predominant Enhancement of Glucose Uptake in Astrocytes versus Neurons during Activation of the Somatosensory Cortex

Glucose is the primary energetic substrate of the brain, and measurements of its metabolism are the basis of major functional cerebral imaging methods. Contrary to the general view that neurons are fueled solely by glucose in proportion to their energetic needs, recent in vitro and ex vivo analyses suggest that glucose preferentially feeds astrocytes. However, the cellular fate of glucose in the intact brain has not yet been directly observed. We have used a real-time method for measuring glucose uptake in astrocytes and neurons in vivo in male rats by imaging the trafficking of the nonmetabolizable glucose analog 6-deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-aminoglucose (6-NBDG) using two-photon microscopy. During resting conditions we found that astrocytes and neurons both take up 6-NBDG at the same rate in the barrel cortex of the rat. However, during intense neuronal activity triggered by whisker stimulation, astrocytes rapidly accelerated their uptake, whereas neuronal uptake remained almost unchanged. After the stimulation period, astrocytes returned to their preactivation rates of uptake paralleling the neuronal rate of uptake. These observations suggest that glucose is taken up primarily by astrocytes, supporting the view that functional imaging experiments based on glucose analogs extraction may predominantly reflect the metabolic activity of the astrocytic network.

Intrinsic Circuit Organization and Theta–Gamma Oscillation Dynamics in the Entorhinal Cortex of the Rat

A thorough knowledge of the intrinsic circuit properties of the entorhinal cortex (EC) and the temporal dynamics these circuits support is essential for understanding how information is exchanged between the hippocampus and neocortex. Using intracellular and extracellular recordings in the anesthetized rat and anatomical reconstruction of single cells, we found that EC5 and EC2 principal neurons form large axonal networks mainly within their layers, interconnected by the more vertically organized axon trees of EC3 pyramidal cells. Principal cells showed layer-specific unique membrane properties and contributed differentially to theta and gamma oscillations. EC2 principal cells were most strongly phase modulated by EC theta. The multiple gamma oscillators, present in the various EC layers, were temporally coordinated by the phase of theta waves. Putative interneurons in all EC layers fired relatively synchronously within the theta cycle, coinciding with the maximum power of gamma oscillation. The special wiring architecture and unique membrane properties of EC neurons may underlie their behaviorally distinct firing patterns in the waking animal.

Stiripentol, a Putative Antiepileptic Drug, Enhances the Duration of Opening of GABAA‐Receptor Channels

Summary:  Purpose: Stiripentol (STP) is currently an efficient drug for add‐on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown.

A systematic framework for functional connectivity measures

Various methods have been proposed to characterize the functional connectivity between nodes in a network measured with different modalities (electrophysiology, functional magnetic resonance imaging etc.). Since different measures of functional connectivity yield different results for the same dataset, it is important to assess when and how they can be used. In this work, we provide a systematic framework for evaluating the performance of a large range of functional connectivity measures—based upon a comprehensive portfolio of models generating measurable responses. Specifically, we benchmarked 42 methods using 10,000 simulated datasets from 5 different types of generative models with different connectivity structures. Since all functional connectivity methods require the setting of some parameters (window size and number, model order etc.), we first optimized these parameters using performance criteria based upon (threshold free) ROC analysis. We then evaluated the performance of the methods on data simulated with different types of models. Finally, we assessed the performance of the methods against different levels of signal-to-noise ratios and network configurations. A MATLAB toolbox is provided to perform such analyses using other methods and simulated datasets.

Persistent epileptiform activity induced by low Mg2+ in intact immature brain structures

We have determined the properties of seizures induced in vitro during the first postnatal days using intact rat cortico‐hippocampal formations (CHFs) and extracellular recordings. Two main patterns of activity were generated by nominally Mg2+‐free ACSF in hippocampal and cortical regions: ictal‐like events (ILEs) and late recurrent interictal discharges (LRDs). They were elicited at distinct developmental periods and displayed different pharmacological properties. ILEs were first observed in P1 CHFs 52 ± 7 min after application of low‐Mg2+ ACSF (frequency 1.5 ± 0.3 h‐1, duration 86 ± 3 s). There is a progressive age‐dependent maturation of ILEs characterized by a decrease in their onset and an increase in their frequency and duration. ILEs were abolished by d‐APV and Mg2+ ions. From P7, ILEs were followed by LRDs that appeared 89 ± 8 min after application of low‐Mg2+ ACSF (frequency ≈ 1 Hz, duration 0.66 s, amplitude 0.31 ± 0.03 mV). LRDs were no longer sensitive to d‐APV or Mg2+ ions and persisted for at least 24 h in low‐Mg2+ or in normal ACSF. ILEs and LRDs were synchronized in limbic and cortical regions with 10–40 ms latency between the onsets of seizures. Using a double chamber that enables independent superfusion of two interconnected CHFs, we report that ILEs and LRDs generated in one CHF propagated readily to the other one that was being kept in ACSF. Therefore, at a critical period of brain development, recurrent seizures induce a permanent form of hyperactivity in intact brain structures and this preparation provides a unique opportunity to study the consequences of seizures at early developmental stages.

Effects of antiepileptic drugs on refractory seizures in the intact immature corticohippocampal formation in vitro

Summary:  Purpose: We developed a new in vitro preparation of immature rats, in which intact corticohippocampal formations (CHFs) depleted in magnesium ions become progressively epileptic. The better to characterize this model, we examined the effects of 14 antiepileptic drugs (AEDs) currently used in clinical practice.

Localized Neuron Stimulation with Organic Electrochemical Transistors on Delaminating Depth Probes.

Organic electrochemical transistors are integrated on depth probes to achieve localized electrical stimulation of neurons. The probes feature a mechanical delamination process which leaves only a 4 μm thick film with embedded transistors inside the brain. This considerably reduces probe invasiveness and correspondingly improves future brain-machine interfaces.

Autoclave Sterilization of PEDOT:PSS Electrophysiology Devices

Autoclaving, the most widely available sterilization method, is applied to poly(3,4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) electrophysiology devices. The process does not harm morphology or electrical properties, while it effectively kills E. coli intentionally cultured on the devices. This finding paves the way to widespread introduction of PEDOT:PSS electrophysiology devices to the clinic.