Witold J. Lipski

A Subpopulation of Neurons in the Medial Prefrontal Cortex Encodes Emotional Learning with Burst and Frequency Codes through a Dopamine D4 Receptor-Dependent Basolateral Amygdala Input

The basolateral nucleus of the amygdala (BLA) and medial prefrontal cortex (mPFC) are involved importantly in the processing and encoding of emotionally salient learned associations. Here, we examined the possible role of the mPFC in the acquisition and encoding of emotional associative learning at the behavioral and single-neuron level. A subpopulation of neurons in the mPFC that received monosynaptic and orthodromic inputs from the BLA demonstrated strong associative responding to odors paired previously with footshock by increasing spontaneous activity and bursting activity. This occurred specifically in response to postconditioning presentations of the footshock-paired odors but not to odors presented in the absence of footshock. In contrast, mPFC neurons that failed to respond to BLA stimulation showed no associative responding. Systemic or intra-mPFC blockade of dopamine (DA) D4 receptors prevented this emotional associative learning in neurons of the mPFC and blocked the expression of olfactory conditioned fear. These results demonstrate that individual neurons in the mPFC that receive a functional input from the BLA actively encode emotional learning and that this process depends on DA D4 receptor stimulation in the mPFC.

Network Effects of Deep Brain Stimulation

The ability to differentially alter specific brain functions via deep brain stimulation (DBS) represents a monumental advance in clinical neuroscience, as well as within medicine as a whole. Despite the efficacy of DBS in the treatment of movement disorders, for which it is often the gold-standard therapy when medical management becomes inadequate, the mechanisms through which DBS in various brain targets produces therapeutic effects is still not well understood. This limited knowledge is a barrier to improving efficacy and reducing side effects in clinical brain stimulation. A field of study related to assessing the network effects of DBS is gradually emerging that promises to reveal aspects of the underlying pathophysiology of various brain disorders and their response to DBS that will be critical to advancing the field. This review summarizes the nascent literature related to network effects of DBS measured by cerebral blood flow and metabolic imaging, functional imaging, and electrophysiology (scalp and intracranial electroencephalography and magnetoencephalography) in order to establish a framework for future studies.

Movement-related dynamics of cortical oscillations in Parkinson’s disease and essential tremor

Recent electrocorticography data have demonstrated excessive coupling of beta-phase to gamma-amplitude in primary motor cortex and that deep brain stimulation facilitates motor improvement by decreasing baseline phase-amplitude coupling. However, both the dynamic modulation of phase-amplitude coupling during movement and the general cortical neurophysiology of other movement disorders, such as essential tremor, are relatively unexplored. To clarify the relationship of these interactions in cortical oscillatory activity to movement and disease state, we recorded local field potentials from hand sensorimotor cortex using subdural electrocorticography during a visually cued, incentivized handgrip task in subjects with Parkinsons disease (n = 11), with essential tremor (n = 9) and without a movement disorder (n = 6). We demonstrate that abnormal coupling of the phase of low frequency oscillations to the amplitude of gamma oscillations is not specific to Parkinsons disease, but also occurs in essential tremor, most prominently for the coupling of alpha to gamma oscillations. Movement kinematics were not significantly different between these groups, allowing us to show for the first time that robust alpha and beta desynchronization is a shared feature of sensorimotor cortical activity in Parkinsons disease and essential tremor, with the greatest high-beta desynchronization occurring in Parkinsons disease and the greatest alpha desynchronization occurring in essential tremor. We also show that the spatial extent of cortical phase-amplitude decoupling during movement is much greater in subjects with Parkinsons disease and essential tremor than in subjects without a movement disorder. These findings suggest that subjects with Parkinsons disease and essential tremor can produce movements that are kinematically similar to those of subjects without a movement disorder by reducing excess sensorimotor cortical phase-amplitude coupling that is characteristic of these diseases.

Activation and inhibition of neurons in the hippocampal ventral subiculum by norepinephrine and locus coeruleus stimulation.

The ventral subiculum (vSub) has been implicated in a wide range of neurocognitive functions, including responses to fear, stress, and anxiety. The vSub receives dense noradrenergic (NE) inputs from the locus coeruleus (LC), and the LC-NE system is heavily implicated in attention and is known to be activated by stressors. However, the way in which the neurons in the vSub respond to activation of the LC-NE is not well understood. In this study, the direct LC innervation of the vSub was investigated. The effect of norepinephrine (NE) on single vSub neurons was examined using microiontophoresis combined with electrophysiological recordings in anesthetized rats, and this response compared with the effect of electrical stimulation of the LC. Iontophoretic NE inhibited all vSub neurons tested, whereas LC stimulation inhibited 16% and activated 38% of neurons. Inhibition was mediated primarily by alpha-2 receptors, whereas activation was mediated by beta-adrenergic receptors. Furthermore, this effect was not mediated via the LC-basolateral amygdala (BLA) pathway, because BLA inactivation did not block LC stimulation-evoked activation of the vSub. These results indicate that the LC-NE system is a potent modulator of vSub activity. Based on these findings, stress-induced activation of the LC-NE system is expected to evoke inhibition and activation in the vSub, both of which may contribute to stress adaptation, whereas an imbalance of this system may lead to pathological stress responses in mental disorders.

An inexpensive, charge-balanced rodent deep brain stimulation device: a step-by-step guide to its procurement and construction.

BACKGROUND Despite there being a relatively large number of methods papers which detail specifically the development of stimulation devices, only a small number of reports involve the application of these devices in freely moving animals. To date multiple preclinical neural stimulators have been designed and described but have failed to make an impact on the methods employed by the majority of laboratories studying DBS. Thus, the overwhelming majority of DBS studies are still performed by tethering the subject to an external stimulator. We believe that the low adoption rate of previously described methods is a result of the complexity of replicating and implementing these methods. NEW METHOD Here were describe both the design and procurement of a simple and inexpensive stimulator designed to be compatible with commonly used, commercially available electrodes (Plastics 1). RESULTS This system is initially programmable in frequency, pulsewidth and current amplitude, and delivers biphasic, charge-balanced output to two independent electrodes. COMPARISON WITH EXISTING METHOD(S) It is easy to implement requiring neither subcutaneous implantation nor custom-made electrodes and has been optimized for either direct mounting to the head or for use with rodent jackets. CONCLUSIONS This device is inexpensive and universally accessible, facilitating high throughput, low cost, long-term rodent deep brain stimulation experiments.

Three-dimensional localization of cortical electrodes in deep brain stimulation surgery from intraoperative fluoroscopy

Electrophysiological recordings from subdural electrocorticography (ECoG) electrodes implanted temporarily during deep brain stimulation (DBS) surgeries offer a unique opportunity to record cortical activity for research purposes. The optimal utilization of this important research method relies on accurate and robust localization of ECoG electrodes, and intraoperative fluoroscopy is often the only imaging modality available to visualize electrode locations. However, the localization of a three-dimensional electrode position using a two-dimensional fluoroscopic image is problematic due to the lost dimension orthogonal to the fluoroscopic image, a parallax distortion implicit to fluoroscopy, and variability of visible skull contour among fluoroscopic images. Here, we present a method to project electrodes visible on the fluoroscopic image onto a reconstructed cortical surface by leveraging numerous common landmarks to translate, rotate, and scale coregistered computed tomography (CT) and magnetic resonance imaging (MRI) reconstructed surfaces in order to recreate the coordinate framework in which the fluoroscopic image was acquired, while accounting for parallax distortion. Validation of this approach demonstrated high precision with an average total Euclidian distance between three independent reviewers of 1.65±0.68mm across 8 patients and 82 electrodes. Spatial accuracy was confirmed by correspondence between recorded neural activity over sensorimotor cortex during hand movement. This semi-automated interface reliably estimates the location of temporarily implanted subdural ECoG electrodes visible on intraoperative fluoroscopy to a cortical surface.

Detection of high-frequency oscillations by hybrid depth electrodes in standard clinical intracranial EEG recordings.

High-frequency oscillations (HFOs) have been proposed as a novel marker for epileptogenic tissue, spurring tremendous research interest into the characterization of these transient events. A wealth of continuously recorded intracranial electroencephalographic (iEEG) data is currently available from patients undergoing invasive monitoring for the surgical treatment of epilepsy. In contrast to data recorded on research-customized recording systems, data from clinical acquisition systems remain an underutilized resource for HFO detection in most centers. The effective and reliable use of this clinically obtained data would be an important advance in the ongoing study of HFOs and their relationship to ictogenesis. The diagnostic utility of HFOs ultimately will be limited by the ability of clinicians to detect these brief, sporadic, and low amplitude events in an electrically noisy clinical environment. Indeed, one of the most significant factors limiting the use of such clinical recordings for research purposes is their low signal to noise ratio, especially in the higher frequency bands. In order to investigate the presence of HFOs in clinical data, we first obtained continuous intracranial recordings in a typical clinical environment using a commercially available, commonly utilized data acquisition system and “off the shelf” hybrid macro-/micro-depth electrodes. These data were then inspected for the presence of HFOs using semi-automated methods and expert manual review. With targeted removal of noise frequency content, HFOs were detected on both macro- and micro-contacts, and preferentially localized to seizure onset zones. HFOs detected by the offline, semi-automated method were also validated in the clinical viewer, demonstrating that (1) this clinical system allows for the visualization of HFOs and (2) with effective signal processing, clinical recordings can yield valuable information for offline analysis.

Sensing-enabled hippocampal deep brain stimulation in idiopathic nonhuman primate epilepsy

Epilepsy is a debilitating condition affecting 1% of the population worldwide. Medications fail to control seizures in at least 30% of patients, and deep brain stimulation (DBS) is a promising alternative treatment. A modified clinical DBS hardware platform was recently described (PC+S) allowing long-term recording of electrical brain activity such that effects of DBS on neural networks can be examined. This study reports the first use of this device to characterize idiopathic epilepsy and assess the effects of stimulation in a nonhuman primate (NHP). Clinical DBS electrodes were implanted in the hippocampus of an epileptic NHP bilaterally, and baseline local field potential (LFP) recordings were collected for seizure characterization with the PC+S. Real-time automatic detection of ictal events was demonstrated and validated by concurrent visual observation of seizure behavior. Seizures consisted of large-amplitude 8- to 25-Hz oscillations originating from the right hemisphere and quickly generalizing, with an average occurrence of 0.71 ± 0.15 seizures/day. Various stimulation parameters resulted in suppression of LFP activity or in seizure induction during stimulation under ketamine anesthesia. Chronic stimulation in the awake animal was studied to evaluate how seizure activity was affected by stimulation configurations that suppressed broadband LFPs in acute experiments. This is the first electrophysiological characterization of epilepsy using a next-generation clinical DBS system that offers the ability to record and analyze neural signals from a chronically implanted stimulating electrode. These results will direct further development of this technology and ultimately provide insight into therapeutic mechanisms of DBS for epilepsy.

Footshock-induced responses in ventral subiculum neurons are mediated by locus coeruleus noradrenergic afferents

The ventral subiculum (vSub) of the hippocampus is critically involved in mediating the forebrains response to stress, particularly with regard to psychogenic stressors. Stress, in turn, is known to aggravate many psychiatric conditions including schizophrenia, depression, anxiety, and drug abuse. Pathological alterations in hippocampal function have been identified in all these disorders; thus, it is of interest to understand how stress affects this brain region. The vSub receives dense projections from the stress-related locus coeruleus (LC); however, it is not known what role this input plays in signaling stressful stimuli. In this study, the direct LC innervation of the vSub was investigated as a potential mediator of stress responses in this region. To examine responses to an acute stressor, the effect of footshock on single vSub neurons was tested in rats. Footshock inhibited 13%, and activated 48% of neurons in this region. Importantly, responses to footshock were correlated with LC stimulation-evoked responses in single neurons, and LC inactivation blocked these responses. Furthermore, prazosin, an alpha-1 antagonist, reversed footshock-evoked inhibition, revealing an underlying activation. Inactivation of the basolateral amygdala (BLA) did not block phasic footshock-evoked activation; however, it reduced tonic activity in the vSub. These results suggest that the LC NE system plays an important role in mediating stress responses in the vSub. Footshock evokes both inhibition and excitation in the vSub, by activating noradrenergic inputs from the LC. These responses may contribute to stress adaptation; while an imbalance of this system may lead to pathological stress responses in mental disorders.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinsons disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.