Updating perspectives on spinal cord function: motor coordination, timing, relational processing, and memory below the brain.

Those studying neural systems within the brain have historically assumed that lower-level processes in the spinal cord act in a mechanical manner, to relay afferent signals and execute motor commands. From this view, abstracting temporal and environmental relations is the province of the brain. Here we review work conducted over the last 50 years that challenges this perspective, demonstrating that mechanisms within the spinal cord can organize coordinated behavior (stepping), induce a lasting change in how pain (nociceptive) signals are processed, abstract stimulus-stimulus (Pavlovian) and response-outcome (instrumental) relations, and infer whether stimuli occur in a random or regular manner. The mechanisms that underlie these processes depend upon signal pathways (e.g., NMDA receptor mediated plasticity) analogous to those implicated in brain-dependent learning and memory. New data show that spinal cord injury (SCI) can enable plasticity within the spinal cord by reducing the inhibitory effect of GABA. It is suggested that the signals relayed to the brain may contain information about environmental relations and that spinal cord systems can coordinate action in response to descending signals from the brain. We further suggest that the study of stimulus processing, learning, memory, and cognitive-like processing in the spinal cord can inform our views of brain function, providing an attractive model system. Most importantly, the work has revealed new avenues of treatment for those that have suffered a SCI.

Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain.

The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl- in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl- through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.

Behavioral studies of spinal conditioning: The spinal cord is smarter than you think it is.

In 1988 Robert Rescorla published an article in the Annual Review of Neuroscience that addressed the circumstances under which learning occurs, some key methodological issues, and what constitutes an example of learning. The article has inspired a generation of neuroscientists, opening the door to a wider range of learning phenomena. After reviewing the historical context for his article, its key points are briefly reviewed. The perspective outlined enabled the study of learning in simpler preparations, such as the spinal cord. The period after 1988 revealed that pain (nociceptive) stimuli can induce a lasting sensitization of spinal cord circuits, laying down a kind of memory mediated by signal pathways analogous to those implicated in brain dependent learning and memory. Evidence suggests that the spinal cord is sensitive to instrumental response-outcome (R-O) relations, that learning can induce a peripheral modification (muscle memory) that helps maintain the learned response, and that learning can promote adaptive plasticity (a form of metaplasticity). Conversely, exposure to uncontrollable stimulation disables the capacity to learn. Spinal cord neurons can also abstract that stimuli occur in a regular (predictable) manner, a capacity that appears linked to a neural oscillator (central pattern generator). Disrupting communication with the brain has been shown to transform how GABA affects neuronal function (an example of ionic plasticity), releasing a brake that enables plasticity. We conclude by presenting a framework for understanding these findings and the implications for the broader study of learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Role of Descending Serotonergic Fibers in the Development of Pathophysiology after Spinal Cord Injury (SCI): Contribution to Chronic Pain, Spasticity, and Autonomic Dysreflexia.

As the nervous system develops, nerve fibers from the brain form descending tracts that regulate the execution of motor behavior within the spinal cord, incoming sensory signals, and capacity to change (plasticity). How these fibers affect function depends upon the transmitter released, the receptor system engaged, and the pattern of neural innervation. The current review focuses upon the neurotransmitter serotonin (5-HT) and its capacity to dampen (inhibit) neural excitation. A brief review of key anatomical details, receptor types, and pharmacology is provided. The paper then considers how damage to descending serotonergic fibers contributes to pathophysiology after spinal cord injury (SCI). The loss of serotonergic fibers removes an inhibitory brake that enables plasticity and neural excitation. In this state, noxious stimulation can induce a form of over-excitation that sensitizes pain (nociceptive) circuits, a modification that can contribute to the development of chronic pain. Over time, the loss of serotonergic fibers allows prolonged motor drive (spasticity) to develop and removes a regulatory brake on autonomic function, which enables bouts of unregulated sympathetic activity (autonomic dysreflexia). Recent research has shown that the loss of descending serotonergic activity is accompanied by a shift in how the neurotransmitter GABA affects neural activity, reducing its inhibitory effect. Treatments that target the loss of inhibition could have therapeutic benefit.

Learning to promote recovery after spinal cord injury.

The present review explores the concept of learning within the context of neurorehabilitation after spinal cord injury (SCI). The aim of physical therapy and neurorehabilitation is to bring about a lasting change in function-to encourage learning. Traditionally, it was assumed that the adult spinal cord is hardwired-immutable and incapable of learning. Research has shown that neurons within the lower (lumbosacral) spinal cord can support learning after communication with the brain has been disrupted by means of a thoracic transection. Noxious stimulation can sensitize nociceptive circuits within the spinal cord, engaging signal pathways analogous to those implicated in brain-dependent learning and memory. After a spinal contusion injury, pain input can fuel hemorrhage, increase the area of tissue loss (secondary injury), and undermine long-term recovery. Neurons within the spinal cord are sensitive to environmental relations. This learning has a metaplastic effect that counters neural over-excitation and promotes adaptive learning through an up-regulation of brain-derived neurotrophic factor (BDNF). Exposure to rhythmic stimulation, treadmill training, and cycling also enhances the expression of BDNF and counters the development of nociceptive sensitization. SCI appears to enable plastic potential within the spinal cord by down-regulating the Cl- co-transporter KCC2, which reduces GABAergic inhibition. This enables learning, but also fuels over-excitation and nociceptive sensitization. Pairing epidural stimulation with activation of motor pathways also promotes recovery after SCI. Stimulating motoneurons in response to activity within the motor cortex, or a targeted muscle, has a similar effect. It is suggested that a neurofunctionalist approach can foster the discovery of processes that impact spinal function and how they may be harnessed to foster recovery after SCI.

Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms.

BACKGROUND: Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. METHODS: Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. RESULTS: Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. CONCLUSIONS: These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

The initiation of cannabis use in adolescence is predicted by sex-specific psychosocial and neurobiological features.

Cannabis use initiated during adolescence might precipitate negative consequences in adulthood. Thus, predicting adolescent cannabis use prior to any exposure will inform the aetiology of substance abuse by disentangling predictors from consequences of use. In this prediction study, data were drawn from the IMAGEN sample, a longitudinal study of adolescence. All selected participants (n = 1,581) were cannabis-naïve at age 14. Those reporting any cannabis use (out of six ordinal use levels) by age 16 were included in the outcome group (N = 365, males n = 207). Cannabis-naïve participants at age 14 and 16 were included in the comparison group (N = 1,216, males n = 538). Psychosocial, brain and genetic features were measured at age 14 prior to any exposure. Cross-validated regularized logistic regressions for each use level by sex were used to perform feature selection and obtain prediction error statistics on independent observations. Predictors were probed for sex- and drug-specificity using post-hoc logistic regressions. Models reliably predicted use as indicated by satisfactory prediction error statistics, and contained psychosocial features common to both sexes. However, males and females exhibited distinct brain predictors that failed to predict use in the opposite sex or predict binge drinking in independent samples of same-sex participants. Collapsed across sex, genetic variation on catecholamine and opioid receptors marginally predicted use. Using machine learning techniques applied to a large multimodal dataset, we identified a risk profile containing psychosocial and sex-specific brain prognostic markers, which were likely to precede and influence cannabis initiation.

Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation.

OBJECTIVES: Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity. METHODS: Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders. RESULTS: For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants' own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders. CONCLUSIONS: Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018, 24, 91-103).

Response inhibition and addiction medicine: from use to abstinence.

Historically, neuroscientific research into addiction has emphasized affective and reinforcement mechanisms as the essential elements underlying the pursuit of drugs, their abuse, and difficulties associated with abstinence. However, research over the last decade or so has shown that cognitive control systems, associated largely but not exclusively with the frontal lobes, are also important contributors to drug use behaviors. Here, we focus on inhibitory control and its contribution to both current use and abstinence. A body of evidence points to impaired inhibitory abilities across a range of drugs of abuse. Typically, studies suggest that substance-abusing individuals are characterized by relative hypoactivity in brain systems underlying inhibitory control. In contrast, abstinent users tend to show either normal or supernormal levels of activity in the same systems attesting to the importance of inhibitory control in suppressing the drug use urges that plague attempts at abstinence. In this chapter, the brain and behavioral basis of response inhibition will be reviewed, with a focus on neuroimaging studies of response inhibition in current and abstinent drug abusers.

Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat.

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n=70) of 14-year olds with a history of cannabis use to a group (n=70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.