Treatments to Combat Opiate Dependence

The current opioid epidemic is a pressing public health concern that has been difficult to address because there is no generally accepted hypothesis to explain the underlying neurophysiological mechanism(s) that lead to tolerance and withdrawal, which in turn could serve as the basis for developing therapeutic interventions. As a step to developing such a unifying mechanistic hypothesis we studied both the electrophysiological firing patterns of individual neurons and behaviors indicative of tolerance and withdrawal in rats following chronic administration of morphine. Neuronal activity recordings from the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), thalamus, hypothalamus, hippocampus (HIPP), Amygdala (AMYG) and caudate nucleus (CN) following exposure of repetitive (chronic) morphine produced a new baseline pattern of neuronal firing rates, which we refer to as an “opioid-induced pattern” in the mesocorticolimbic neuronal activity circuit, which is thought to be involved in mediating the “reward” effects of opioid and other drugs of abuse. These changes in neuronal firing rate was paralleled by behavioral changes indicative of the development of dependence such as tolerance and withdrawal suggesting a possible cause-effect relationship between the opioid induced pattern change of baseline neuronal firing and the development of opioid tolerance and withdrawal. Briefly, (i) morphine produces a new baseline pattern of neuronal firing (i.e., an “opioid-induced pattern”), (ii) there is an intrinsic neurophysiological mechanism that seeks to maintain newly established patterns of baseline neuronal firing once established, (iii) continued morphine administration maintains the new pattern of baseline neuronal activity so that withdrawal behaviors do not occur, but (iv) eventual discontinuation of the drug leads to opioid withdrawal symptoms. Consistent with this proposed hypothesis, co-administration of the immunomodulator such as interferon, cyclosporin and cortisol attenuated both the development of an altered baseline pattern of neuronal firing and the parallel behavioral changes. This observation suggests that immunomodifiers treatment to morphine dependence subject restore the neuronal firing rate to its pre-morphine baseline and thus alleviate the withdrawal symptoms that make is so difficult for addicts to discontinue opioid use. The studies in this review describe in more detail the findings that led to our proposed hypothesis for the underlying neurophysiological basis of the development of opioid tolerance and withdrawal and the possible use of immunomodulators to decrease the development of dependence and thereby attenuate withdrawal symptoms that make it so difficult for addicts to discontinue drug use. Repetitive use of opioids results in dependence on the drug, a complex condition that is considered to be an opiate use disorder (OUD). The reduction or cessation of opioid consumption leads to severe withdrawal behaviors. The degree of opiate dependence can be assessed by the intensity of the withdrawal behavior. To prevent this devastating opiate withdrawal syndrome, the subject will continue to take the drug. Success in modifying the withdrawal behavior may shed light on the dynamics of OUD and help to curb the opiate epidemic. Classical therapeutic addiction research has focused on cellular and molecular alterations within neurons and their neuronal circuits. As such, most of the pharmacotherapies for opioid addiction are designed to target the neuronal processes known to be affected by drug intake. In addition to the pivotal role of neurons in the initiation, transition, and maintenance of opioid dependence, the glial cells within the central nervous system are also of particular importance. According to some studies, 60 to 80% of the cellular brain is composed of glial cells. Recent studies have shown that glial cells participate in synaptogenesis, neuronal excitability, and neurotransmission. Following opioid exposure, glial cells demonstrate robust changes in their morphology and physiology in key central nervous system regions known to contribute to drug dependence. They play a pivotal role in opioid-addiction like behaviors. Glial cells are also part of the immune system. This review summarizes studies demonstrating that the immune system participates in the expression of opiate withdrawal and that a single dose of immunological substances such as α-interferon, cyclosporine, or cortisol significantly attenuates the severity of the naloxone-induced withdrawal symptoms in opioid-dependent animals. These preclinical studies provide a new approach to treat opiate dependence using immunomodulators that do not belong to the opiate family. We hope that this review will encourage translational studies to use immunomodulators in combating the opioid epidemic and save lives.

Frequency-dependent spike-pattern changes in motor cortex during thalamic deep brain stimulation

The network mechanisms of thalamic deep brain stimulation (DBS) are not well understood at the cellular level. This study investigated the neuronal firing rate and pattern changes in the motor cortex resulting from stimulation of the cerebellar-receiving area of the motor thalamus. We showed that there is a nonintuitive relationship between general entropy-based spike-pattern measures and phase-locked regularization to DBS.

Intertrial Variability in Human Corticospinal Activity during Grasp Force Planning

ABSTRACTNeuronal firing rate variability during planning has been found to contribute to trial-to-trial variability in primate behavior. However, in humans, whether planning related mechanisms contribute to trial-to-trial behavioral variability remains unknown. We investigated the time-course of trial-to-trial variability in corticospinal excitability (CSE) using transcranial magnetic stimulation (TMS) while subjects planned to perform a self-paced reach-to-grasp task. We hypothesized that CSE variability will be modulated during task planning and that such a modulation would explain trial-to-trial behavioral variability. Able-bodied individuals were visually cued to plan their grip force before exertion of either 30% or 5% of maximum force on an object. TMS was delivered at different time points following a cue that instructed the force level. We first modeled the relation between CSE magnitude and its variability at rest (n=12) to study the component of CSE variability during task planning that was not related to changes in CSE magnitude (n=12). We found an increase in CSE variability during task planning at 30% but not at 5% of force. This effect was temporally dissociated from the decrease in CSE magnitude. Importantly, the increase in CSE variability during planning explained 64% of inter-individual differences in time to peak force rate trial-to-trial variability. These results were found to be repeatable across studies and robust to different analysis methods. Our findings suggest that the planning-related mechanisms underlying modulation in CSE variability and CSE magnitude are distinct. Notably, the extent of modulation in planning-related variability in corticospinal system within individuals may explain their trial-to-trial behavioral variability.

Direct Electrophysiological Correlates of Body Ownership in Human Cerebral Cortex

Over the past decade, numerous neuroimaging studies based on hemodynamic markers of brain activity have examined the feeling of body ownership using perceptual body-illusions in humans. However, the direct electrophysiological correlates of body ownership at the cortical level remain unexplored. To address this, we studied the rubber hand illusion in 5 patients (3 males and 2 females) implanted with intracranial electrodes measuring cortical surface potentials. Increased high-γ (70–200 Hz) activity, an index of neuronal firing rate, in premotor and intraparietal cortices reflected the feeling of ownership. In both areas, high-γ increases were intimately coupled with the subjective illusion onset and sustained both during and in-between touches. However, intraparietal activity was modulated by tactile stimulation to a higher degree than the premotor cortex through effective connectivity with the hand-somatosensory cortex, which suggests different functional roles. These findings constitute the first intracranial electrophysiological characterization of the rubber hand illusion and extend our understanding of the dynamic mechanisms of body ownership.