Tag: Neuroscience

What is Neuropsychopharmacology?

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Introduction

Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (study of effects of drugs on the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behaviour.

It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of “how” and “why”, and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based treatments. Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behaviour, and sleep behaviour.

Brief History

Drugs such as opium, alcohol, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era knowledge of how the substances actually worked was quite limited, most pharmacological knowledge being more a series of observation than a coherent model. The first half of the 20th century saw psychology and psychiatry as largely phenomenological, in that behaviours or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the behavioural branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as “software” errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields – until several developments after World War II began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as MAO inhibitors, tricyclic antidepressants, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the prefrontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants and both of which often caused the patient great physical and psychological injury.

The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology. This rapidly maturing field shows some degree of flux, as research hypotheses are often restructured based on new information.

Overview

An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neurochemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10-10 M such as found with extrastriatal D1 receptor for dopamine.

One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuropathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These “hyperselective-action” drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximising the efficacy (or technically the potency) of the drug within the clinical target and minimising adverse effects. However, there are some cases when some degree of pharmacological promiscuity is tolerable and even desirable, producing more desirable results than a more selective agent would. An example of this is Vortioxetine, a drug which is not particularly selective as a serotonin reuptake inhibitor, having a significant degree of serotonin modulatory activity, but which has demonstrated reduced discontinuation symptoms (and reduced likelihood of relapse) and greatly reduced incidence of sexual dysfunction, without loss in antidepressant efficacy.

The groundwork is currently being paved for the next generation of pharmacological treatments, which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons – the study of which, in addition to neurotrophic factors, may hold hope for neurodegenerative diseases like Alzheimer’s, Parkinson’s, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.

Neurotransmission

So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device.

By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:

  • The synthesis and storage of neurotransmitter substances;
  • The transport of synaptic vesicles and subsequent release into the synapse;
  • Receptor activation and cascade function; and
  • Transport mechanisms (reuptake) and/or enzyme degradation.

The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterisation of a large number of very specific subtypes of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further “sub-subtypes” exist together with variants, totalling in the hundreds for just these 6 transmitters (refer to serotonin receptor, for example). It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.

It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the transmembrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl−. The concentration differences between the inside and outside of the cell determine the membrane voltage.

Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein coupled processes. Many receptors are found to be pentameric clusters of five transmembrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.

The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expression determines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.

Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.

Drugs

The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. “dirty drug”) and safe to consume. The 2005 Physicians’ Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with “selective serotonin reuptake inhibitors“, or SSRIs which exemplify modern pharmaceuticals. These SSRI antidepressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker anti-psychotics, and GABA agonist tranquilisers (benzodiazepines).

New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the antinarcoleptic action of the drug modafinil which was already being used only a year prior.

The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1 antagonists, and 5HT2c antagonists. Another is the proposal of new routes of exploration for antipsychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.

Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. Phencyclidine has been found to cause cell death in striatopallidal cells and abnormal vacuolisation in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons (Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself). As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.

Neural Circuits

It is a not-so-recent discovery that many functions of the brain are somewhat localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioural, and genetic correlates of receptor action, completing the knowledge of neural signalling (refer to Human Cognome Project). The signal paths of neurons are hyperorganised beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts.

Almost all drugs with a known potential for abuse have been found to modulate activity (directly or indirectly) in the mesolimbic dopamine system, which includes and connects the ventral tegmental area in the midbrain to the hippocampus, medial prefrontal cortex, and amygdala in the forebrain; as well as the nucleus accumbens in the ventral striatum of the basal ganglia. In particular, the nucleus accumbens (NAc) plays an important role in integrating experiential memory from the hippocampus, emotion from the amygdala, and contextual information from the PFC to help associate particular stimuli or behaviours with feelings of pleasure and reward; continuous activation of this reward indicator system by an addictive drug can also cause previously neutral stimuli to be encoded as cues that the brain is about to receive a reward. This happens via the selective release of dopamine, a neurotransmitter responsible for feelings of euphoria and pleasure. The use of dopaminergic drugs alters the amount of dopamine released throughout the mesolimbic system, and regular or excessive use of the drug can result in a long-term downregulation of dopamine signalling, even after an individual stops ingesting the drug. This can lead the individual to engage in mild to extreme drug-seeking behaviours as the brain begins to regularly expect the increased presence of dopamine and the accompanying feelings of euphoria, but how problematic this is depends highly on the drug and the situation.

Significant progress has been made on central mechanisms of certain hallucinogenic drugs. It is at this point known with relative certainty that the primary shared effects of a broad pharmacological group of hallucinogens, sometimes called the “classical psychedelics”, can be attributed largely to agonism of serotonin receptors. The 5HT2A receptor, which seems to be the most critical receptor for psychedelic activity, and the 5HT2C receptor, which is a significant target of most psychedelics but which has no clear role in hallucinogenesis, are involved by releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. 5HT2A activity has a net pro-dopaminergic effect, whereas 5HT2C receptor agonism has an inhibitory effect on dopaminergic activity, particularly in the prefrontal cortex. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory postsynaptic potentials, a process antagonised by serotonin itself through 5HT1 receptors, which may explain why SSRIs and other serotonin-affecting drugs do not normally cause a patient to hallucinate. However, the fact that many classical psychedelics do in fact have significant affinity for 5HT1 receptors throws this claim into question. The head twitch response, a test used for assessing classical psychedelic activity in rodents, is produced by serotonin itself only in the presence of beta-Arrestins, but is triggered by classical psychedelics independent of beta-Arrestin recruitment. This may better explain the difference between the pharmacology of serotonergic neurotransmission (even if promoted by drugs such as SSRIs) and that of classical psychedelics. Newer findings, however, indicate that binding to the 5HT2A-mGlu2 heterodimer is also necessary for classical psychedelic activity. This, too, may be relevant to the pharmacological differences between the two. While early in the history of psychedelic drug research it was assumed that these hallucinations were comparable to those produced by psychosis and thus that classical psychedelics could serve as a model of psychosis, it is important to note that modern neuropsychopharmacological knowledge of psychosis has progressed significantly since then, and we now know that psychosis shows little similarity to the effects of classical psychedelics in mechanism, reported experience or most other respects aside from the surface similarity of “hallucination”.

Circadian rhythm, or sleep/wake cycling, is centred in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsin cells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABAergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibres. The output of the SCG, stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of melatonin which “entrains” the 24-hour cycle of SCN activity. The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.

Research

Research in the field of neuropsychopharmacology encompasses a wide range of objectives. These might include the study of a new chemical compound for potentially beneficial cognitive or behavioural effects, or the study of an old chemical compound in order to better understand its mechanism of action at the cell and neural circuit levels. For example, the addictive stimulant drug cocaine has long been known to act upon the reward system in the brain, increasing dopamine and norepinephrine levels and inducing euphoria for a short time. More recently published studies however have gone deeper than the circuit level and found that a particular G-protein coupled receptor complex called A2AR-D2R-Sigma1R is formed in the NAc following cocaine usage; this complex reduces D2R signalling in the mesolimbic pathway and may be a contributing factor to cocaine addiction. Other cutting-edge studies have focused on genetics to identify specific biomarkers that may predict an individual’s specific reactions or degree of response to a drug or their tendency to develop addictions in the future. These findings are important because they provide detailed insight into the neural circuitry involved in drug use and help refine old as well as develop new treatment methods for disorders or addictions. Different treatment-related studies are investigating the potential role of peptide nucleic acids in treating Parkinson’s disease and schizophrenia while still others are attempting to establish previously unknown neural correlates underlying certain phenomena.

Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes European Neuropsychopharmacology, and as part of the Reed Elsevier Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002, a recent comprehensive collected work of the ACNP, “Neuropsychopharmacology: The Fifth Generation of Progress” was compiled. It is one measure of the state of knowledge in 2002, and might be said to represent a landmark in the century-long goal to establish the basic neurobiological principles which govern the actions of the brain.

Many other journals exist which contain relevant information such as Neuroscience. Some of them are listed at Brown University Library.

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What is Psychoneuroimmunology?

Published on by Andrew MarshallLeave a comment

Introduction

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioural medicine, infectious diseases, endocrinology, and rheumatology.

The main interests of PNI are the interactions between the nervous and immune systems and the relationships between mental processes and health. PNI studies, among other things, the physiological functioning of the neuroimmune system in health and disease; disorders of the neuroimmune system (autoimmune diseases; hypersensitivities; immune deficiency); and the physical, chemical and physiological characteristics of the components of the neuroimmune system in vitro, in situ, and in vivo.

Brief History

Interest in the relationship between psychiatric syndromes or symptoms and immune function has been a consistent theme since the beginning of modern medicine.

Claude Bernard, a French physiologist of the Muséum national d’Histoire naturelle (National Museum of Natural History in English), formulated the concept of the milieu interieur in the mid-1800s. In 1865, Bernard described the perturbation of this internal state: “… there are protective functions of organic elements holding living materials in reserve and maintaining without interruption humidity, heat and other conditions indispensable to vital activity. Sickness and death are only a dislocation or perturbation of that mechanism” (Bernard, 1865). Walter Cannon, a professor of physiology at Harvard University coined the commonly used term, homeostasis, in his book The Wisdom of the Body, 1932, from the Greek word homoios, meaning similar, and stasis, meaning position. In his work with animals, Cannon observed that any change of emotional state in the beast, such as anxiety, distress, or rage, was accompanied by total cessation of movements of the stomach (Bodily Changes in Pain, Hunger, Fear and Rage, 1915). These studies looked into the relationship between the effects of emotions and perceptions on the autonomic nervous system, namely the sympathetic and parasympathetic responses that initiated the recognition of the freeze, fight or flight response. His findings were published from time to time in professional journals, then summed up in book form in The Mechanical Factors of Digestion, published in 1911.

Hans Selye, a student of Johns Hopkins University and McGill University, and a researcher at Université de Montréal, experimented with animals by putting them under different physical and mental adverse conditions and noted that under these difficult conditions the body consistently adapted to heal and recover. Several years of experimentation that formed the empiric foundation of Selye’s concept of the General Adaptation Syndrome. This syndrome consists of an enlargement of the adrenal gland, atrophy of the thymus, spleen, and other lymphoid tissue, and gastric ulcerations.

Selye describes three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance, and a terminal stage of exhaustion and death. This foundational work led to a rich line of research on the biological functioning of glucocorticoids.

Mid-20th century studies of psychiatric patients reported immune alterations in psychotic individuals, including lower numbers of lymphocytes and poorer antibody response to pertussis vaccination, compared with nonpsychiatric control subjects. In 1964, George F. Solomon, from the University of California in Los Angeles, and his research team coined the term “psychoimmunology” and published a landmark paper: “Emotions, immunity, and disease: a speculative theoretical integration.”

Origins

In 1975, Robert Ader and Nicholas Cohen, at the University of Rochester, advanced PNI with their demonstration of classic conditioning of immune function, and they subsequently coined the term “psychoneuroimmunology”. Ader was investigating how long conditioned responses (in the sense of Pavlov’s conditioning of dogs to drool when they heard a bell ring) might last in laboratory rats. To condition the rats, he used a combination of saccharin-laced water (the conditioned stimulus) and the drug Cytoxan, which unconditionally induces nausea and taste aversion and suppression of immune function. Ader was surprised to discover that after conditioning, just feeding the rats saccharin-laced water was associated with the death of some animals and he proposed that they had been immunosuppressed after receiving the conditioned stimulus. Ader (a psychologist) and Cohen (an immunologist) directly tested this hypothesis by deliberately immunizing conditioned and unconditioned animals, exposing these and other control groups to the conditioned taste stimulus, and then measuring the amount of antibody produced. The highly reproducible results revealed that conditioned rats exposed to the conditioned stimulus were indeed immunosuppressed. In other words, a signal via the nervous system (taste) was affecting immune function. This was one of the first scientific experiments that demonstrated that the nervous system can affect the immune system.

In the 1970s, Hugo Besedovsky, Adriana del Rey and Ernst Sorkin, working in Switzerland, reported multi-directional immune-neuro-endocrine interactions, since they show that not only the brain can influence immune processes but also the immune response itself can affect the brain and neuroendocrine mechanisms. They found that the immune responses to innocuous antigens triggers an increase in the activity of hypothalamic neurons and hormonal and autonomic nerve responses that are relevant for immunoregulation and are integrated at brain levels. On these bases, they proposed that the immune system acts as a sensorial receptor organ that, besides its peripheral effects, can communicate to the brain and associated neuro-endocrine structures its state of activity. These investigators also identified products from immune cells, later characterized as cytokines, that mediate this immune-brain communication.

In 1981, David L. Felten, then working at the Indiana University School of Medicine, and his colleague JM Williams, discovered a network of nerves leading to blood vessels as well as cells of the immune system. The researchers also found nerves in the thymus and spleen terminating near clusters of lymphocytes, macrophages, and mast cells, all of which help control immune function. This discovery provided one of the first indications of how neuro-immune interaction occurs.

Ader, Cohen, and Felten went on to edit the groundbreaking book Psychoneuroimmunology in 1981, which laid out the underlying premise that the brain and immune system represent a single, integrated system of defence.

In 1985, research by neuropharmacologist Candace Pert, of the National Institutes of Health at Georgetown University, revealed that neuropeptide-specific receptors are present on the cell walls of both the brain and the immune system. The discovery that neuropeptides and neurotransmitters act directly upon the immune system shows their close association with emotions and suggests mechanisms through which emotions, from the limbic system, and immunology are deeply interdependent. Showing that the immune and endocrine systems are modulated not only by the brain but also by the central nervous system itself affected the understanding of emotions, as well as disease.

Contemporary advances in psychiatry, immunology, neurology, and other integrated disciplines of medicine has fostered enormous growth for PNI. The mechanisms underlying behaviourally induced alterations of immune function, and immune alterations inducing behavioural changes, are likely to have clinical and therapeutic implications that will not be fully appreciated until more is known about the extent of these interrelationships in normal and pathophysiological states.

The Immune-Brain Loop

PNI research looks for the exact mechanisms by which specific neuroimmune effects are achieved. Evidence for nervous-immunological interactions exist at multiple biological levels.

The immune system and the brain communicate through signalling pathways. The brain and the immune system are the two major adaptive systems of the body. Two major pathways are involved in this cross-talk: the Hypothalamic-pituitary-adrenal axis (HPA axis), and the sympathetic nervous system (SNS), via the sympathetic-adrenal-medullary axis (SAM axis). The activation of SNS during an immune response might be aimed to localise the inflammatory response.

The body’s primary stress management system is the HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body’s cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases, with evidence from meta-analyses indicating that different types/duration of stressors and unique personal variables can shape the HPA response. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines.

Molecules called pro-inflammatory cytokines, which include interleukin-1 (IL-1), Interleukin-2 (IL-2), interleukin-6 (IL-6), Interleukin-12 (IL-12), Interferon-gamma (IFN-Gamma) and tumour necrosis factor alpha (TNF-alpha) can affect brain growth as well as neuronal function. Circulating immune cells such as macrophages, as well as glial cells (microglia and astrocytes) secrete these molecules. Cytokine regulation of hypothalamic function is an active area of research for the treatment of anxiety-related disorders.

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis. Like the stress response, the inflammatory reaction is crucial for survival. Systemic inflammatory reaction results in stimulation of four major programs:

  • The acute-phase reaction.
  • Sickness behaviour.
  • The pain programme.
  • The stress response.

These are mediated by the HPA axis and the SNS. Common human diseases such as allergy, autoimmunity, chronic infections and sepsis are characterised by a dysregulation of the pro-inflammatory versus anti-inflammatory and T helper (Th1) versus (Th2) cytokine balance. Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, in addition to autoimmune hypersensitivity and chronic infections.

Chronic secretion of stress hormones, glucocorticoids (GCs) and catecholamines (CAs), as a result of disease, may reduce the effect of neurotransmitters, including serotonin, norepinephrine and dopamine, or other receptors in the brain, thereby leading to the dysregulation of neurohormones. Under stimulation, norepinephrine is released from the sympathetic nerve terminals in organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released norepinephrine, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells.

Glucocorticoids also inhibit the further secretion of corticotropin-releasing hormone from the hypothalamus and ACTH from the pituitary (negative feedback). Under certain conditions stress hormones may facilitate inflammation through induction of signalling pathways and through activation of the Corticotropin-releasing hormone.

These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioural parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health, developing into a “systemic anti-inflammatory feedback” and/or “hyperactivity” of the local pro-inflammatory factors which may contribute to the pathogenesis of disease.

This systemic or neuro-inflammation and neuroimmune activation have been shown to play a role in the aetiology of a variety of neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease, multiple sclerosis, pain, and AIDS-associated dementia. However, cytokines and chemokines also modulate central nervous system (CNS) function in the absence of overt immunological, physiological, or psychological challenges.

Psychoneuroimmunological Effects

There are now sufficient data to conclude that immune modulation by psychosocial stressors and/or interventions can lead to actual health changes. Although changes related to infectious disease and wound healing have provided the strongest evidence to date, the clinical importance of immunological dysregulation is highlighted by increased risks across diverse conditions and diseases. For example, stressors can produce profound health consequences. In one epidemiological study, all-cause mortality increased in the month following a severe stressor – the death of a spouse. Theorists propose that stressful events trigger cognitive and affective responses which, in turn, induce sympathetic nervous system and endocrine changes, and these ultimately impair immune function. Potential health consequences are broad, but include rates of infection HIV progression cancer incidence and progression, and high rates of infant mortality.

Understanding Stress and Immune Function

Stress is thought to affect immune function through emotional and/or behavioural manifestations such as anxiety, fear, tension, anger and sadness and physiological changes such as heart rate, blood pressure, and sweating. Researchers have suggested that these changes are beneficial if they are of limited duration, but when stress is chronic, the system is unable to maintain equilibrium or homeostasis; the body remains in a state of arousal, where digestion is slower to reactivate or does not reactivate properly, often resulting in indigestion. Furthermore, blood pressure stays at higher levels.

In one of the earlier PNI studies, which was published in 1960, subjects were led to believe that they had accidentally caused serious injury to a companion through misuse of explosives. Since then decades of research resulted in two large meta-analyses, which showed consistent immune dysregulation in healthy people who are experiencing stress.

In the first meta-analysis by Herbert and Cohen in 1993, they examined 38 studies of stressful events and immune function in healthy adults. They included studies of acute laboratory stressors (e.g. a speech task), short-term naturalistic stressors (e.g. medical examinations), and long-term naturalistic stressors (e.g. divorce, bereavement, caregiving, unemployment). They found consistent stress-related increases in numbers of total white blood cells, as well as decreases in the numbers of helper T cells, suppressor T cells, and cytotoxic T cells, B cells, and natural killer cells (NK). They also reported stress-related decreases in NK and T cell function, and T cell proliferative responses to phytohaemagglutinin [PHA] and concanavalin A [Con A]. These effects were consistent for short-term and long-term naturalistic stressors, but not laboratory stressors.

In the second meta-analysis by Zorrilla et al. in 2001, they replicated Herbert and Cohen’s meta-analysis. Using the same study selection procedures, they analysed 75 studies of stressors and human immunity. Naturalistic stressors were associated with increases in number of circulating neutrophils, decreases in number and percentages of total T cells and helper T cells, and decreases in percentages of natural killer cell (NK) cells and cytotoxic T cell lymphocytes. They also replicated Herbert and Cohen’s finding of stress-related decreases in NKCC and T cell mitogen proliferation to phytohaemagglutinin (PHA) and concanavalin A (Con A).

A study done by the American Psychological Association did an experiment on rats, where they applied electrical shocks to a rat, and saw how interleukin-1 was released directly into the brain. Interleukin-1 is the same cytokine released when a macrophage chews on a bacterium, which then travels up the vagus nerve, creating a state of heightened immune activity, and behavioural changes.

More recently, there has been increasing interest in the links between interpersonal stressors and immune function. For example, marital conflict, loneliness, caring for a person with a chronic medical condition, and other forms on interpersonal stress dysregulate immune function.

Communication Between the Brain and Immune System

  • Stimulation of brain sites alters immunity (stressed animals have altered immune systems).
  • Damage to brain hemispheres alters immunity (hemispheric lateralisation effects).
  • Immune cells produce cytokines that act on the CNS.
  • Immune cells respond to signals from the CNS.

Communication Between Neuroendocrine and Immune System

  • Glucocorticoids and catecholamines influence immune cells.
  • Hypothalamic Pituitary Adrenal axis releases the needed hormones to support the immune system.
  • Activity of the immune system is correlated with neurochemical/neuroendocrine activity of brain cells.

Connections Between Glucocorticoids and Immune System

  • Anti-inflammatory hormones that enhance the organism’s response to a stressor.
  • Prevent the overreaction of the body’s own defence system.
  • Overactivation of glucocorticoid receptors can lead to health risks.
  • Regulators of the immune system.
  • Affect cell growth, proliferation and differentiation.
  • Cause immunosuppression which can lead to an extended amount of time fighting off infections.
  • High basal levels of cortisol are associated with a higher risk of infection.
  • Suppress cell adhesion, antigen presentation, chemotaxis and cytotoxicity.
  • Increase apoptosis.

Corticotropin-Releasing Hormone (CRH)

Release of corticotropin-releasing hormone (CRH) from the hypothalamus is influenced by stress.

  • CRH is a major regulator of the HPA axis/stress axis.
  • CRH Regulates secretion of Adrenocorticotropic hormone (ACTH).
  • CRH is widely distributed in the brain and periphery.
  • CRH also regulates the actions of the Autonomic nervous system ANS and immune system.

Furthermore, stressors that enhance the release of CRH suppress the function of the immune system; conversely, stressors that depress CRH release potentiate immunity.

  • Central mediated since peripheral administration of CRH antagonist does not affect immunosuppression.
  • HPA axis/stress axis responds consistently to stressors that are new, unpredictable and that have low-perceived control.
  • As cortisol reaches an appropriate level in response to the stressor, it deregulates the activity of the hippocampus, hypothalamus, and pituitary gland which results in less production of cortisol.

Relationships Between Prefrontal Cortex Activation and Cellular Senescence

  • Psychological stress is regulated by the prefrontal cortex (PFC).
  • The PFC modulates vagal activity.
  • Prefrontally modulated and vagally mediated cholinergic input to the spleen reduces inflammatory responses.

Pharmaceutical Advances

Glutamate agonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, GABA agonists (including opioids and cannabinoids), COX inhibitors, acetylcholine modulators, melatonin analogues (such as Ramelton), adenosine receptor antagonists and several miscellaneous drugs (including biologics like Passiflora edulis) are being studied for their psychoneuroimmunological effects.

For example, SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine, dopamine and cannabinoid receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psychoneuroimmunological process. Antidepressants have also been shown to suppress TH1 upregulation.

Tricyclic and dual serotonergic-noradrenergic reuptake inhibition by SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally. According to recent evidences antidepressants also seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing Interferon-beta (IFN-beta) release or augmenting NK activity in depressed patients.

These studies warrant investigation of antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimal pharmacotherapy in many diseases. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

The endocannabinoid system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery. The endocannabinoid-induced modulation of stress-related behaviours appears to be mediated, at least in part, through the regulation of the serotoninergic system, by which cannabinoid CB1 receptors modulate the excitability of dorsal raphe serotonin neurons. Data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of chronic, unpredictable stress (CUS) on CB1 receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.

The increase in amygdalar CB1 receptor binding following imipramine treatment is consistent with prior studies which collectively demonstrate that several treatments which are beneficial to depression, such as electroconvulsive shock and tricyclic antidepressant treatment, increase CB1 receptor activity in subcortical limbic structures, such as the hippocampus, amygdala and hypothalamus. And preclinical studies have demonstrated the CB1 receptor is required for the behavioural effects of noradrenergic based antidepressants but is dispensable for the behavioural effect of serotonergic based antidepressants.

Extrapolating from the observations that positive emotional experiences boost the immune system, Roberts speculates that intensely positive emotional experiences – sometimes brought about during mystical experiences occasioned by psychedelic medicines – may boost the immune system powerfully. Research on salivary IgA supports this hypothesis, but experimental testing has not been done.

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What is Clinical Neuroscience?

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Introduction

Clinical neuroscience is a branch of neuroscience that focuses on the scientific study of fundamental mechanisms that underlie diseases and disorders of the brain and central nervous system. It seeks to develop new ways of conceptualising and diagnosing such disorders and ultimately of developing novel treatments.

Background

A clinical neuroscientist is a scientist who has specialised knowledge in the field. Not all clinicians are clinical neuroscientists. Clinicians and scientists – including psychiatrists, neurologists, clinical psychologists, neuroscientists, and other specialists – use basic research findings from neuroscience in general and clinical neuroscience in particular to develop diagnostic methods and ways to prevent and treat neurobiological disorders. Such disorders include addiction, Alzheimer’s disease, amyotrophic lateral sclerosis, anxiety disorders, attention deficit hyperactivity disorder, autism, bipolar disorder, brain tumours, depression, Down syndrome, dyslexia, epilepsy, Huntington’s disease, multiple sclerosis, neurological AIDS, neurological trauma, pain, obsessive-compulsive disorder, Parkinson’s disease, schizophrenia, sleep disorders, stroke and Tourette syndrome.

While neurology, neurosurgery and psychiatry are the main medical specialties that use neuroscientific information, other specialties such as cognitive neuroscience, neuroradiology, neuropathology, ophthalmology, otorhinolaryngology, anaesthesiology and rehabilitation medicine can contribute to the discipline. Integration of the neuroscience perspective alongside other traditions like psychotherapy, social psychiatry or social psychology will become increasingly important.

One Mind for Research

The “One Mind for Research” forum was a convention held in Boston, Massachusetts on 23 to 25 May 2011 that produced the blueprint document A Ten-Year Plan for Neuroscience: From Molecules to Brain Health. Leading neuroscience researchers and practitioners in the United States contributed to the creation of this document, in which 17 key areas of opportunities are listed under the Clinical Neuroscience section. These include the following:

  • Rethinking curricula to break down intellectual silos.
  • Training translational neuroscientists and clinical investigators.
  • Investigating biomarkers.
  • Improving psychiatric diagnosis.
  • Developing a “Framingham Study of Brain Disorders” (i.e. longitudinal cohort for central nervous system disease).
  • Identifying developmental risk factors and producing effective interventions.
  • Discovering new treatments for pain, including neuropathic pain.
  • Treating disorders of neural signalling and pathological synchrony.
  • Treating disorders of immunity or inflammation.
  • Treating metabolic and mitochondrial disorders.
  • Developing new treatments for depression.
  • Treating addictive disorders.
  • Improving treatment of schizophrenia.
  • Preventing and treating cerebrovascular disease.
  • Achieving personalized medicine.
  • Understanding shared mechanisms of neurodegeneration.
  • Advancing anaesthesia.

In particular, it advocates for better integrated and scientifically driven curricula for practitioners, and it recommends that such curricula be shared among neurologists, psychiatrists, psychologists, neurosurgeons and neuroradiologists.

Given the various ethical, legal and societal implications for healthcare practitioners arising from advances in neuroscience, the University of Pennsylvania inaugurated the Penn Conference on Clinical Neuroscience and Society in July 2011.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Clinical_neuroscience >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

Who was Benjamin Libet?

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Introduction

Benjamin Libet (12 April 1916 to 23 July 2007) was an American neuroscientist who was a pioneer in the field of human consciousness.

Libet was a researcher in the physiology department of the University of California, San Francisco. In 2003, he was the first recipient of the Virtual Nobel Prize in Psychology from the University of Klagenfurt, “for his pioneering achievements in the experimental investigation of consciousness, initiation of action, and free will”.

Life

Benjamin Libet, Neuroscientist.

He was the son of Ukrainian Jewish immigrants. Gamer Libitsky, his paternal grandfather, came to America in 1865 from a town called Brusilov in Ukraine. His mother, Anna Charovsky, emigrated from Kiev in 1913. His parents first met in Chicago. They were married in 1915, and somewhat over nine months later Benjamin was born. He had a brother Meyer, and a sister Dorothy. Libet attended a public elementary school and John Marshall High School. Libet graduated from the University of Chicago, where he studied with Ralph Gerard.

In the 1970s, Libet was involved in research into neural activity and sensation thresholds. His initial investigations involved determining how much activation at specific sites in the brain was required to trigger artificial somatic sensations, relying on routine psychophysical procedures. This work soon crossed into an investigation into human consciousness; his most famous experiment was meant to demonstrate that the unconscious electrical processes in the brain called Bereitschaftspotential (or readiness potential) discovered by Lüder Deecke and Hans Helmut Kornhuber in 1964 precede conscious decisions to perform volitional, spontaneous acts, implying that unconscious neuronal processes precede and potentially cause volitional acts which are retrospectively felt to be consciously motivated by the subject. The experiment has caused controversy not only because it challenges the belief in free will, but also due to a criticism of its implicit assumptions. It has also inspired further study of the neuroscience of free will.

Volitional Acts and Readiness Potential

Equipment

To gauge the relation between unconscious readiness potential and subjective feelings of volition and action, Libet required an objective method of marking the subject’s conscious experience of the will to perform an action in time, and afterward comparing this information with data recording the brain’s electrical activity during the same interval. For this, Libet required specialised pieces of equipment.

The first of these was the cathode ray oscilloscope, an instrument typically used to graph the amplitude and frequency of electrical signals. With a few adjustments, however, the oscilloscope could be made to act as a timer: instead of displaying a series of waves, the output was a single dot that could be made to travel in a circular motion, similar to the movements of a second hand around a clock face. This timer was set so that the time it took for the dot to travel between intervals marked on the oscilloscope was approximately forty-three milliseconds. As the angular velocity of the dot remained constant, any change in distance could easily be converted into the time it took to travel that distance.

To monitor brain activity during the same period, Libet used an electroencephalogram (EEG). The EEG uses small electrodes placed at various points on the scalp that measure neuronal activity in the cortex, the outermost portion of the brain, which is associated with higher cognition. The transmission of electrical signals across regions of the cortex causes differences in measured voltage across EEG electrodes. These differences in voltage reflect changes in neuronal activity in specific areas of the cortex.

To measure the actual time of the voluntary motor act, an electromyograph (EMG) recorded the muscle movement using electrodes on the skin over the activated muscle of the forearm. The EMG time was taken as the zero time relative to which all other times were calculated.

Methods

Researchers carrying out Libet’s procedure would ask each participant to sit at a desk in front of the oscilloscope timer. They would affix the EEG electrodes to the participant’s scalp, and would then instruct the subject to carry out some small, simple motor activity, such as pressing a button, or flexing a finger or wrist, within a certain time frame. No limits were placed on the number of times the subject could perform the action within this period.

During the experiment, the subject would be asked to note the position of the dot on the oscilloscope timer when “he/she was first aware of the wish or urge to act” (control tests with Libet’s equipment demonstrated a comfortable margin of error of only -50 milliseconds). Pressing the button also recorded the position of the dot on the oscillator, this time electronically. By comparing the marked time of the button’s pushing and the subject’s conscious decision to act, researchers were able to calculate the total time of the trial from the subject’s initial volition through to the resultant action. On average, approximately two hundred milliseconds elapsed between the first appearance of conscious will to press the button and the act of pressing it.

Researchers also analysed EEG recordings for each trial with respect to the timing of the action. It was noted that brain activity involved in the initiation of the action, primarily centred in the secondary motor cortex, occurred, on average, approximately five hundred milliseconds before the trial ended with the pushing of the button. That is to say, researchers recorded mounting brain activity related to the resultant action as many as three hundred milliseconds before subjects reported the first awareness of conscious will to act. In other words, apparently conscious decisions to act were preceded by an unconscious buildup of electrical activity within the brain – the change in EEG signals reflecting this buildup came to be called Bereitschaftspotential or readiness potential. As of 2008, the upcoming outcome of a decision could be found in study of the brain activity in the prefrontal and parietal cortex up to 7 seconds before the subject was aware of their decision.

Implications of Libet’s Experiments

There is no majority agreement about the interpretation or the significance of Libet’s experiments. However, Libet’s experiments suggest to some that unconscious processes in the brain are the true initiator of volitional acts, and free will therefore plays no part in their initiation. If unconscious brain processes have already taken steps to initiate an action before consciousness is aware of any desire to perform it, the causal role of consciousness in volition is all but eliminated, according to this interpretation. For instance, Susan Blackmore’s interpretation is “that conscious experience takes some time to build up and is much too slow to be responsible for making things happen.”

Such a conclusion would be overdrawn as in a subsequent run of experiments, Libet found that even after the awareness of the decision to push the button had happened, people still had the capability to veto the decision and not to push the button. So they still had the capability to refrain from the decision that had earlier been made. Some therefore take this brain impulse to push the button to suggest just a readiness potential which the subject may either then go along with or may veto. So the person still has power over his or her decision.

For this reason, Libet himself regards his experimental results to be entirely compatible with the notion of free will. He finds that conscious volition is exercised in the form of ‘the power of veto’ (sometimes called “free won’t”); the idea that conscious acquiescence is required to allow the unconscious buildup of the readiness potential to be actualized as a movement. While consciousness plays no part in the instigation of volitional acts, Libet suggested that it may still have a part to play in suppressing or withholding certain acts instigated by the unconscious. Libet noted that everyone has experienced the withholding from performing an unconscious urge. Since the subjective experience of the conscious will to act preceded the action by only 200 milliseconds, this leaves consciousness only 100-150 milliseconds to veto an action (this is because the final 20 milliseconds prior to an act are occupied by the activation of the spinal motor neurones by the primary motor cortex, and the margin of error indicated by tests utilising the oscillator must also be considered). However, Max Velmans has argued: “Libet has shown that the experienced intention to perform an act is preceded by cerebral initiation. Why should the experienced decision to veto that intention, or to actively or passively promote its completion, be any different?”

In a study published in 2012, Aaron Schurger, Jacobo D. Sitt, and Stanislas Dehaene proposed that the occurrence of the readiness potentials observed in Libet-type experiments is stochastically occasioned by ongoing spontaneous subthreshold fluctuations in neural activity, rather than an unconscious goal-directed operation.

Libet’s experiments have received support from other research related to the Neuroscience of free will.

Reactions by Dualist Philosophers

The German philosopher Uwe Meixner commented:

“For making an informed decision, the self needs to be conscious of the facts relevant to the decision prior to making the decision; but…the self certainly does not need to be conscious of making the decision at the very same time it makes it…the consciousness of a state of affairs P being (presently) the case is always somewhat later than the actual fact of P’s being the case…”

When one is speaking to another individual, as a result of the limited velocity of light signals and the limited velocity of sound waves and the limited velocity of nerve signals, what one is experiencing as now is always slightly in the past. No person ever has a definite present awareness of what is occurring around them. There is a small time delay due to the limited velocity of these many different signals that is indiscernible to people because it is extremely short. Meixner also says, “it is hardly surprising that the consciousness of making a decision is no exception to this general rule, which is due to the dependence of consciousness on neurophysiology.”

Just as nothing that is actually presently there can be observed because of the limited velocity of light but events as they are just a little in the past can be observed, in the same way people do not have a consciousness of their own decisions simultaneously with their making them but they have it undetectedly afterwards.

If the mind has the power to think without being causally determined, then all it requires to do in order to make accountable, knowledgeable, free decisions is consciousness of the pertinent facts before its decision making. However, the mind does not require to be aware or conscious of the decision itself at the same it makes that decision.

It has been suggested that consciousness is merely a side-effect of neuronal functions, an epiphenomenon of brain states. Libet’s experiments are proffered in support of this theory; our reports of conscious instigation of our own acts are, in this view, a mistake of retrospection. However, some dualist philosophers have disputed this conclusion:

In short, the [neuronal] causes and correlates of conscious experience should not be confused with their ontology … the only evidence about what conscious experiences are like comes from first-person sources, which consistently suggest consciousness to be something other than or additional to neuronal activity.

A more general criticism from a dualist-interactionist perspective has been raised by Alexander Batthyany who points out that Libet asked his subjects to merely “let the urge [to move] appear on its own at any time without any pre-planning or concentration on when to act”. According to Batthyany, neither reductionist nor non-reductionist agency theories claim that urges which appear on their own are suitable examples of (allegedly) consciously caused events because one cannot passively wait for an urge to occur while at the same time being the one who is consciously bringing it about. Libet’s results thus cannot be interpreted to provide empirical evidence in favour of agency reductionism, since non-reductionist theories, even including dualist interactionism, would predict the very same experimental results.

Timing Issues

Daniel Dennett argues that no clear conclusion about volition can be derived from Libet’s experiment because of ambiguities in the timings of the different events involved. Libet tells when the readiness potential occurs objectively, using electrodes, but relies on the subject reporting the position of the hand of a clock to determine when the conscious decision was made. As Dennett points out, this is only a report of where it seems to the subject that various things come together, not of the objective time at which they actually occur.

Suppose Libet knows that your readiness potential peaked at millisecond 6,810 of the experimental trial, and the clock dot was straight down (which is what you reported you saw) at millisecond 7,005. How many milliseconds should he have to add to this number to get the time you were conscious of it? The light gets from your clock face to your eyeball almost instantaneously, but the path of the signals from retina through lateral geniculate nucleus to striate cortex takes 5 to 10 milliseconds – a paltry fraction of the 300 milliseconds offset, but how much longer does it take them to get to you (Or are you located in the striate cortex?). The visual signals have to be processed before they arrive at wherever they need to arrive for you to make a conscious decision of simultaneity. Libet’s method presupposes, in short, that we can locate the intersection of two trajectories:

  • The rising-to-consciousness of signals representing the decision to flick.
  • The rising to consciousness of signals representing successive clock-face orientations.

So that these events occur side-by-side as it were in place where their simultaneity can be noted.

Subjective Backward Referral or “Antedating” of Sensory Experience

Libet’s early theory, resting on study of stimuli and sensation, was found bizarre by some commentators, including Patricia Churchland, due to the apparent idea of backward causation. Libet argued that data suggested that we retrospectively “antedate” the beginning of a sensation to the moment of the primary neuronal response. People interpreted Libet’s work on stimulus and sensation in a number of different ways. John Eccles presented Libet’s work as suggesting a backward step in time made by a non-physical mind. Edoardo Bisiach (1988) described Eccles as tendentious, but commented:

This is indeed the conclusion that the authors (Libet, et al.) themselves seem to be willing to force upon the reader. … They dispute an alternative explanation, suggested by Mackay in a discussion with Libet (1979, p. 219) to the effect that ‘the subjective referral backwards in time may be due to an illusory judgment made by the subject when he reports the timings’, and more significant, Libet, et al. (1979, p. 220) hint at ‘serious though not insurmountable difficulties’ for the identity theory (of mind and matter) caused by their data.

Libet later concluded that there appeared to be no neural mechanism that could be viewed as directly mediating or accounting for the subjective sensory referrals backward in time [emphasis Libet’s]. Libet postulated that the primary evoked potential (EP) serves as a “time marker”. The EP is a sharp positive potential appearing in the appropriate sensory region of the brain about 25 milliseconds after a skin stimulus. Libet’s experiments demonstrated that there is an automatic subjective referral of the conscious experience backwards in time to this time marker. The skin sensation does not enter our conscious awareness until about 500 milliseconds after the skin stimulus, but we subjectively feel that the sensation occurred at the time of the stimulus.

For Libet, these subjective referrals would appear to be purely a mental function with no corresponding neural basis in the brain. Indeed, this suggestion can be more broadly generalized:

The transformation from neuronal patterns to a subjective representation would appear to develop in a mental sphere that has emerged from that neuronal pattern. … My view of mental subjective function is that it is an emergent property of appropriate brain functions. The conscious mental cannot exist without the brain processes that give rise to it. However, having emerged from brain activities as a unique ‘property’ of that physical system, the mental can exhibit phenomena not evident in the neural brain that produced it.

Conscious Mental Field Theory

In the later part of his career, Libet proposed a theory of the conscious mental field (CMF) to explain how the mental arises from the physical brain. The two main motivations prompting this proposal were:

  1. The phenomenon of the unity of subjective conscious experience; and
  2. The phenomenon that conscious mental function appears to influence nerve cell activity.

Regarding the unity of conscious experience, it was increasingly evident to Libet that many functions of the cortex are localised, even to a microscopic level in a region of the brain, and yet the conscious experiences related to these areas are integrated and unified. We do not experience an infinite array of individual events but rather a unitary integrated consciousness, for example, with no gaps in spatial and coloured images. For Libet, some unifying process or phenomenon likely mediates the transformation of localised, particularised neuronal representations into our unified conscious experience. This process seemed to be best accountable in a mental sphere that appears to emerge from the neural events, namely, the conscious mental field.

The CMF is the mediator between the physical activities of nerve cells and the emergence of subjective experience. Thus the CMF is the entity in which unified subjective experience is present and provides the causal ability to affect or alter some neuronal functions. Libet proposed the CMF as a “property” of an emergent phenomenon of the brain; it does not exist without the brain but emerges from the appropriate system of neural activity. This proposal is related to electromagnetic theories of consciousness.

To test the proposed causal ability of the CMF to affect or alter neuronal functions, Libet proposed an experimental design, which would surgically isolate a slab of cerebral cortex (in a patient for whom such a procedure was therapeutically required). If electrical stimulation of the isolated cortex can elicit an introspective report by the subject, the CMF must be able to activate appropriate cerebral areas in order to produce the verbal report. This result would demonstrate directly that a conscious mental field could affect neuronal functions in a way that would account for the activity of the conscious will. Detailed description of the proposed experimental test is as follows:

A small slab of sensory cortex (subserving any modality) is neuronally isolated but kept viable by making all the cortical cuts subpially. This allows the blood vessels in the pia to project into the isolated slab and provide blood flow from the arterial branches that dip vertically into the cortex. The prediction is that electrical stimulation of the sensory slab will produce a subjective response reportable by the subject. That is, activity in the isolated slab can contribute by producing its own portion of the CMF.

Libet further elaborated on CMF:

The CMF is not a Cartesian dualistic phenomenon; it is not separable from the brain. Rather, it is proposed to be a localizable system property produced by appropriate neuronal activities, and it cannot exist without them. Again, it is not a ghost in the machine. But, as a system produced by billions of nerve cell actions, it can have properties not directly predictable from these neuronal activities. It is a non-physical phenomenon, like the subjective experience that it represents. The process by which the CMF arises from its contributing elements is not describable. It must simply be regarded as a new fundamental given phenomenon in nature, which is different from other fundamental givens, like gravity or electromagnetism.

Tributes

Dr. Robert W. Doty, professor of Neurobiology and Anatomy at the University of Rochester:

Benjamin Libet’s discoveries are of extraordinary interest. His is almost the only approach yet to yield any credible evidence of how conscious awareness is produced by the brain. Libet’s work is unique, and speaks to questions asked by all humankind.

Dr. Susan J. Blackmore, visiting lecturer at the University of the West of England, Bristol:

Many philosophers and scientists have argued that free will is an illusion. Unlike all of them, Benjamin Libet found a way to test it.

In Popular Culture

Libet and his research into the delay is referenced several times in song titles by musical artist the Caretaker, who was influenced by some of his work. The 2011 album An Empty Bliss Beyond This World contains a song called “Libet’s Delay”, which went on to be one of the more popular tracks from it. The Caretaker’s final release, Everywhere at the End of Time, contains the songs “Back There Benjamin,” (Referring to his first name) “Libet’s All Joyful Camaraderie” and “Libet Delay”, with the latter being a far more twisted, distorted version of the original “Libet’s Delay”. Also, the 2019 extra album Everywhere, an Empty Bliss includes a track named “Benjamin Beyond Bliss”.

What is Affective Neuroscience?

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Introduction

Affective neuroscience is the study of the neural mechanisms of emotion.

This interdisciplinary field combines neuroscience with the psychological study of personality, emotion, and mood. The putative existence of ‘basic emotions’ and their defining attributes represents a long lasting and yet unsettled issue in the field.

The term was coined by neuroscientist Jaak Panksepp, at a time when cognitive neuroscience focused on non-emotional cognition, such as attention or memory.

Brain Areas

Emotions are thought to be related to activity in brain areas that direct our attention, motivate our behaviour, and choose the significance of what is going on around us. Pioneering work by Paul Broca (1878), James Papez (1937), and Paul D. MacLean (1952) suggested that emotion is related to a group of structures in the centre of the brain called the limbic system, which includes the hypothalamus, cingulate cortex, hippocampi, and other structures. Research has shown that limbic structures are directly related to emotion, but other structures have been found to be of greater emotional relevance.

The following brain structures are currently thought to be involved in emotion:

Limbic System

  • Amygdala:
    • The amygdalae are two small, round structures located anterior to the hippocampi near the temporal poles.
    • The amygdalae are involved in detecting and learning which parts of our surroundings are important and have emotional significance.
    • They are critical for the production of emotion, and may be particularly so for negative emotions, especially fear.
    • Multiple studies have shown amygdala activation when perceiving a potential threat; various circuits allow the amygdala to use related past memories to better judge the possible threat.
  • Thalamus:
    • The thalamus is involved in relaying sensory and motor signals to the cerebral cortex, especially visual stimuli.
    • The thalamus plays an important role in regulating states of sleep and wakefulness.
  • Hypothalamus:
    • The hypothalamus is involved in producing a physical output associated with an emotion as well as in reward circuits.
  • Hippocampus:
    • The hippocampus is a structure of the medial temporal lobes that is mainly involved in memory.
    • It works to form new memories and also connects senses such as visual input, smell or sound to memories.
    • The hippocampus allows long term memories to be stored and retrieves them when necessary.
    • Memories are used within the amygdala to help evaluate stimulae.
  • Fornix:
    • The fornix is the main output pathway from the hippocampus to the mammillary bodies.
    • It has been identified as a main region in controlling spatial memory functions, episodic memory and executive functions.
  • Mammillary body:
    • Mammillary bodies are important for recollective memory.
  • Olfactory bulb:
    • The olfactory bulbs are the first cranial nerves, located on the ventral side of the frontal lobe.
    • They are involved in olfaction, the perception of odours.
  • Cingulate gyrus:
    • The cingulate gyrus is located above the corpus callosum and is usually considered to be part of the limbic system.
    • The parts of the cingulate gyrus have different functions, and are involved with affect, visceromotor control, response selection, skeletomotor control, visuospatial processing, and in memory access.
    • A part of the cingulate gyrus is the anterior cingulate cortex, which is thought to play a central role in attention and behaviourally demanding cognitive tasks.
    • It may be particularly important with regard to conscious, subjective emotional awareness.
    • This region of the brain may play an important role in the initiation of motivated behaviour.
    • The subgenual cingulate is more active during both experimentally induced sadness and during depressive episodes.

Other Brain Structures

  • Basal ganglia:
    • Basal ganglia are groups of nuclei found on either side of the thalamus.
    • Basal ganglia play an important role in motivation, action selection and reward learning.
  • Orbitofrontal cortex:
    • The orbitofrontal cortex is a major structure involved in decision making and the influence by emotion on that decision.
  • Prefrontal cortex:
    • The prefrontal cortex is the front of the brain, behind the forehead and above the eyes.
    • It appears to play a critical role in the regulation of emotion and behaviour by anticipating consequences.
    • It may play an important role in delayed gratification by maintaining emotions over time and organising behaviour toward specific goals.
  • Ventral striatum:
    • The ventral striatum is a group of subcortical structures thought to play an important role in emotion and behaviour.
    • One part of the ventral striatum called the nucleus accumbens is thought to be involved in the experience of pleasure.
    • Individuals with addictions experience increased activity in this area when they encounter the object of their addiction.
  • Insula:
    • The insular cortex is thought to play a critical role in the bodily experience of emotion, as it is connected to other brain structures that regulate the body’s autonomic functions (heart rate, breathing, digestion, etc.).
    • The insula is implicated in empathy and awareness of emotion.
  • Cerebellum:
    • A “Cerebellar Cognitive Affective Syndrome” has been described.
    • Both neuroimaging studies as well as studies following pathological cerebellar lesions (such as a stroke) demonstrate that the cerebellum has a significant role in emotional regulation.
    • Lesion studies have shown that cerebellar dysfunction can attenuate the experience of positive emotions.
    • While these same studies do not show an attenuated response to frightening stimuli, the stimuli did not recruit structures that normally would be activated (such as the amygdala).
    • Rather, alternative structures were activated, such as the ventromedial prefrontal cortex, the anterior cingulate gyrus, and the insula.
    • This may indicate that evolutionary pressure resulted in the development of the cerebellum as a redundant fear-mediating circuit to enhance survival.
    • It may also indicate a regulatory role for the cerebellum in the neural response to rewarding stimuli, such as money, drugs of abuse, and orgasm.
  • Lateral prefrontal cortex.
  • Primary sensorimotor cortex.
  • Temporal cortex.
  • Brainstem.

Right Hemisphere

The right hemisphere has been proposed as directly involved in emotion processing. Scientific theory regarding its role produced several models of emotional functioning. C.K. Mills was an early researcher who proposed a direct link between the right hemisphere and emotion processing, having observed decreased emotion processing in patients with lesions to the right hemisphere. In the late 1980s to early 1990s neocortical structures were shown to have an involvement in emotion. These findings led to the development of the right hemisphere hypothesis and the valence hypothesis.

Right Hemisphere Hypothesis

The right hemisphere hypothesis asserts that the right hemisphere is specialized for the expression and perception of emotion. It has been linked with mental strategies that are nonverbal, synthetic, integrative, holistic, and gestaltic. The right hemisphere is more in touch with subcortical systems of autonomic arousal and attention as demonstrated in patients that have increased spatial neglect when damage affects the right brain versus the left brain. Right hemisphere pathologies have been linked with abnormal patterns of autonomic nervous system responses. These findings would help signify the strong connection of the subcortical brain regions to the right hemisphere.

Valence Hypothesis

The valence hypothesis acknowledges the right hemisphere’s role in emotion, but asserts that it is mainly focused on the processing of negative emotions whereas the left hemisphere processes positive emotions. The two hemispheres have been the subject of much debate. One version states that the right hemisphere processes negative emotion leaving positive emotion to the left brain. A second version suggests that the right hemisphere predominates in experiencing both positive and negative emotion. More recently, the frontal lobe has been the focus of research, asserting that the frontal lobes of both hemispheres are involved in emotions, while the parietal and temporal lobes are involved in the processing of emotion. Decreased right parietal lobe activity has been associated with depression and increased right parietal lobe activity with anxiety arousal. The increasing understanding of the different hemispheres has led to increasingly complicated models, all based on the original valence model.

Cognitive Neuroscience

Despite their interactions, the study of cognition until the late 1990s, excluded emotion and focused on non-emotional processes (e.g. memory, attention, perception, action, problem solving and mental imagery). The study of the neural basis of non-emotional and emotional processes emerged as two separate fields: cognitive neuroscience and affective neuroscience. Emotional and non-emotional processes often involve overlapping neural and mental mechanisms.

Cognitive Neuroscience Tasks in Affective Neuroscience Research

Emotion Go/No-Go

The emotion go/no-go task has been used to study behavioural inhibition, particularly emotional modulation of this inhibition. A derivation of the original go/no-go paradigm, this task involves a combination of affective “go cues”, where the participant must rapidly make a motor response, and affective “no-go cues,” where a response must be withheld. Because “go cues” are more common, the task measures a subject’s ability to inhibit a response under different emotional conditions.

The task is common in tests of emotion regulation, and is often paired with neuroimaging measures to localize relevant brain function in both healthy individuals and those with affective disorders. For example, go/no-go studies converge with other methodology to implicate areas of the prefrontal cortex during inhibition of emotionally valenced stimuli.

Emotional Stroop

The emotional Stroop task, an adaptation to the original Stroop, measures attentional bias to emotional stimuli. Participants must name the ink colour of presented words while ignoring the words’ meanings. In general, participants have more difficulty detaching attention from affectively valenced words, than neutral words. This interference from valenced words is measured by the response latency in naming the colour of neutral words as compared with emotional words.

This task has been often used to test selective attention to threatening and other negatively valenced stimuli, most often in relation to psychopathology. Disorder-specific attentional biases have been found for a variety of mental disorders. For example, participants with spider phobia show a bias to spider-related words but not other negatively valenced words. Similar findings have been attributed to threat words related to other anxiety disorders. However, other studies have questioned these findings. In fact, anxious participants in some studies show the Stroop interference effect for both negative and positive words, when the words are matched for emotionality. This means that the specificity effects for various disorders may be largely attributable to the semantic relation of the words to the concerns of the disorder, rather than their emotionality.

Ekman 60 Faces Task

The Ekman faces task is used to measure emotion recognition of six basic emotions. Black and white photographs of 10 actors (6 male, 4 female) are presented, with each actor displaying each emotion. Participants are usually asked to respond quickly with the name of the displayed emotion. The task is a common tool to study deficits in emotion regulation in patients with dementia, Parkinson’s, and other cognitively degenerative disorders. The task has been used to analyse recognition errors in disorders such as borderline personality disorder, schizophrenia, and bipolar disorder.

Dot Probe (Emotion)

The emotional dot-probe paradigm is a task used to assess selective visual attention to and failure to detach attention from affective stimuli. The paradigm begins with a fixation cross at the centre of a screen. An emotional stimulus and a neutral stimulus appear side by side, after which a dot appears behind either the neutral stimulus (incongruent condition) or the affective stimulus (congruent condition). Participants are asked to indicate when they see this dot, and response latency is measured. Dots that appear on the same side of the screen as the image the participant was looking at will be identified more quickly. Thus, it is possible to discern which object the participant was attending to by subtracting the reaction time to respond to congruent versus incongruent trials.

The best documented research with the dot probe paradigm involves attention to threat related stimuli, such as fearful faces, in individuals with anxiety disorders. Anxious individuals tend to respond more quickly to congruent trials, which may indicate vigilance to threat and/or failure to detach attention from threatening stimuli. A specificity effect of attention has also been noted, with individuals attending selectively to threats related to their particular disorder. For example, those with social phobia selectively attend to social threats but not physical threats. However, this specificity may be even more nuanced. Participants with obsessive-compulsive disorder symptoms initially show attentional bias to compulsive threat, but this bias is attenuated in later trials due to habituation to the threat stimuli.

Fear Potentiated Startle

Fear-potentiated startle (FPS) has been utilised as a psychophysiological index of fear reaction in both animals and humans. FPS is most often assessed through the magnitude of the eyeblink startle reflex, which can be measured by electromyography. This eyeblink reflex is an automatic defensive reaction to an abrupt elicitor, making it an objective indicator of fear. Typical FPS paradigms involve bursts of noise or abrupt flashes of light transmitted while an individual attends to a set of stimuli. Startle reflexes have been shown to be modulated by emotion. For example, healthy participants tend to show enhanced startle responses while viewing negatively valenced images and attenuated startle while viewing positively valenced images, as compared with neutral images.

The startle response to a particular stimulus is greater under conditions of threat. A common example given to indicate this phenomenon is that one’s startle response to a flash of light will be greater when walking in a dangerous neighbourhood at night than it would under safer conditions. In laboratory studies, the threat of receiving shock is enough to potentiate startle, even without any actual shock.

Fear potentiated startle paradigms are often used to study fear learning and extinction in individuals with posttraumatic stress disorder and other anxiety disorders. In fear conditioning studies, an initially neutral stimulus is repeatedly paired with an aversive one, borrowing from classical conditioning. FPS studies have demonstrated that post-traumatic stress disorder patients have enhanced startle responses during both danger cues and neutral/safety cues as compared with healthy participants.

Learning

Affect plays many roles during learning. Deep, emotional attachment to a subject area allows a deeper understanding of the material and therefore, learning occurs and lasts. The emotions evoked when reading in comparison to the emotions portrayed in the content affects comprehension. Someone who is feeling sad understands a sad passage better than someone feeling happy. Therefore, a student’s emotion plays an important role during the learning process.

Emotion can be embodied or perceived from words read on a page or in a facial expression. Neuroimaging studies using fMRI have demonstrated that the same area of the brain that is activated when feeling disgust is activated when observing another’s disgust. In a traditional learning environment, the teacher’s facial expression can play a critical role in language acquisition. Showing a fearful facial expression when reading passages that contain fearful tones facilitates students learning of the meaning of certain vocabulary words and comprehension of the passage.

Models

The neurobiological basis of emotion is still disputed. The existence of basic emotions and their defining attributes represents a long lasting and yet unsettled issue in psychology. The available research suggests that the neurobiological existence of basic emotions is still tenable and heuristically seminal, pending some reformulation.

Basic Emotions

These approaches hypothesize that emotion categories (including happiness, sadness, fear, anger, and disgust) are biologically basic. In this view, emotions are inherited, biologically based modules that cannot be separated into more basic psychological components. Models following this approach hypothesize that all mental states belonging to a single emotional category can be consistently and specifically localised to either a single brain region or a defined network of brain regions. Each basic emotion category also shares other universal characteristics: distinct facial behaviour, physiology, subjective experience and accompanying thoughts and memories.

Psychological Constructionist Approaches

This approach to emotion hypothesizes that emotions like happiness, sadness, fear, anger and disgust (and many others) are constructed mental states that occur when brain systems work together. In this view, networks of brain regions underlie psychological operations (e.g. language, attention, etc.) that interact to produce emotion, perception, and cognition. One psychological operation critical for emotion is the network of brain regions that underlie valence (feeling pleasant/unpleasant) and arousal (feeling activated and energised). Emotions emerge when neural systems underlying different psychological operations interact (not just those involved in valence and arousal), producing distributed patterns of activation across the brain. Because emotions emerge from more basic components, heterogeneity affects each emotion category; for example, a person can experience many different kinds of fear, which feel differently, and which correspond to different neural patterns in the brain.

Meta-Analyses

A meta-analysis is a statistical approach to synthesizing results across multiple studies. Included studies investigated healthy, unmedicated adults and that used subtraction analysis to examine brain areas that were more active during emotional processing than during a neutral (control) condition.

Phan et al. 2002

In the first neuroimaging meta-analysis of emotion, Phan et al. (2002) analysed the results of 55 peer reviewed studies between January 1990 and December 2000 to determine if the emotions of fear, sadness, disgust, anger, and happiness were consistently associated with activity in specific brain regions. All studies used fMRI or PET techniques to investigate higher-order mental processing of emotion (studies of low-order sensory or motor processes were excluded). The authors’ tabulated the number of studies that reported activation in specific brain regions. For each brain region, statistical chi-squared analysis was conducted. Two regions showed a statistically significant association. In the amygdala, 66% of studies inducing fear reported activity in this region, as compared to ~20% of studies inducing happiness, ~15% of studies inducing sadness (with no reported activations for anger or disgust). In the subcallosal cingulate, 46% of studies inducing sadness reported activity in this region, as compared to ~20% inducing happiness and ~20% inducing anger. This pattern of clear discriminability between emotion categories was in fact rare, with other patterns occurring in limbic regions, paralimbic regions, and uni/heteromodal regions. Brain regions implicated across discrete emotion included the basal ganglia (~60% of studies inducing happiness and ~60% of studies inducing disgust reported activity in this region) and medial prefrontal cortex (happiness ~60%, anger ~55%, sadness ~40%, disgust ~40%, and fear ~30%).

Murphy et al. 2003

Murphy, et al. 2003 analysed 106 peer reviewed studies published between January 1994 and December 2001 to examine the evidence for regional specialisation of discrete emotions (fear, disgust, anger, happiness and sadness) across a larger set of studies. Studies included in the meta-analysis measured activity in the whole brain and regions of interest (activity in individual regions of particular interest to the study). 3-D Kolmogorov-Smirnov (KS3) statistics were used to compare rough spatial distributions of 3-D activation patterns to determine if statistically significant activations were specific to particular brain regions for all emotional categories. This pattern of consistently activated, regionally specific activations was identified in four brain regions: amygdala with fear (~40% of studies), insula with disgust (~70%), globus pallidus with disgust (~70%), and lateral orbitofrontal cortex with anger (80%). Other regions showed different patterns of activation across categories. For example, both the dorsal medial prefrontal cortex and the rostral anterior cingulate cortex showed consistent activity across emotions (happiness ~50%, sadness ~50%, anger ~ 40%, fear ~30%, and disgust ~ 20%).

Barrett et al. 2006

Barrett, et al. 2006 examined 161 studies published between 1990 and 2001. The authors compared the consistency and specificity of prior meta-analytic findings specific to each notional basic emotion. Consistent neural patterns were defined by brain regions showing increased activity for a specific emotion (relative to a neutral control condition), regardless of the method of induction used (for example, visual vs. auditory cue). Specific neural patterns were defined as separate circuits for one emotion vs. the other emotions (for example, the fear circuit must be discriminable from the anger circuit, although both may include common brain regions). In general, the results supported Phan et al. and Murphy et al., but not specificity. Consistency was determined through the comparison of chi-squared analyses that revealed whether the proportion of studies reporting activation during one emotion was significantly higher than the proportion of studies reporting activation during the other emotions. Specificity was determined through the comparison of emotion-category brain-localizations by contrasting activations in key regions that were specific to particular emotions. Increased amygdala activation during fear was the most consistently reported across induction methods (but not specific). Both meta-analyses associated the anterior cingulate cortex with sadness, although this finding was less consistent (across induction methods) and was not specific. Both meta-analyses found that disgust was associated with the basal ganglia, but these findings were neither consistent nor specific. Neither consistent nor specific activity was observed across the meta-analyses for anger or happiness. This meta-analysis introduced the concept of the basic, irreducible elements of emotional life as dimensions such as approach and avoidance.

Kober et al. 2008

Kober, et al. 2008 reviewed 162 neuroimaging studies published between 1990-2005 to determine if groups of brain regions showed consistent activation patterns while experiencing an emotion directly and (indirectly) as experienced by another. This analysis used multilevel kernel density analysis (MKDA) to examine fMRI and PET studies, a technique that prevents single studies from dominating the results (particularly if they report multiple nearby peaks) and that enables studies involving more participants to exert more influence upon the results. MKDA was used to establish a neural reference space that includes the set of regions showing consistent increases across all studies. This neural reference space was partitioned into functional groups of brain regions showing similar activation patterns by using multivariate techniques to determine co-activation patterns and then using data-reduction techniques to define the functional groupings, resulting in six groups. The authors discussed each functional group in terms of more basic psychological operations.

GroupRegionsNotes
Core LimbicLeft amygdala, hypothalamus, periaqueductal gray/thalamus regions, and amygdala/ventral striatum/ventral globus pallidus/thalamus regions.Integrative emotional centre that plays a general role in evaluating affective significance.
Lateral ParalimbicVentral anterior insula/frontal operculum/right temporal pole/ posterior orbitofrontal cortex, the anterior insula/ posterior orbitofrontal cortex, the ventral anterior insula/ temporal cortex/ orbitofrontal cortex junction, the midinsula/ dorsal putamen, and the ventral striatum /mid insula/ left hippocampus.Plays a role in motivation, contributing to the general valuation of stimuli and particularly in reward.
Medial Prefrontal CortexDorsal medial prefrontal cortex, pregenual anterior cingulate cortex, and rostral dorsal anterior cingulate cortex.Plays a role in both the generation and regulation of emotion.
Cognitive/ Motor NetworkRight frontal operculum, the right interior frontal gyrus, and the pre-supplementray motor area/ left interior frontal gyrus, regions.Not specific to emotion, but instead appear to play a more general role in information processing and cognitive control.
Occipital/ Visual AssociationV8 and V4 areas of the primary visual cortex, the medial temporal lobe, and the lateral occipital cortex.
Medial PosteriorPosterior cingulate cortex and area V1 of the primary visual cortex.

The authors suggest that these regions play a joint role in visual processing and attention to emotional stimuli.

Vytal et al. 2010

Vytal, et al. 2010 examined 83 neuroimaging studies published between 1993-2008 to examine whether neuroimaging evidence supports biologically discrete, basic emotions (i.e. fear, anger, disgust, happiness, and sadness). Consistency analyses identified brain regions associated with individual emotions. Discriminability analyses identified brain regions that were differentially active under contrasting pairs of emotions. This meta-analysis examined PET or fMRI studies that reported whole brain analyses identifying significant activations for at least one of the five emotions relative to a neutral or control condition. The authors used activation likelihood estimation (ALE) to perform spatially sensitive, voxel-wise (sensitive to the spatial properties of voxels) statistical comparisons across studies. This technique allows for direct statistical comparison between activation maps associated with each discrete emotion. Thus, discriminability between the five discrete emotion categories was assessed on a more precise spatial scale than in prior meta-analyses.

Consistency was first assessed by comparing the cross-study ALE map for each emotion to ALE maps generated by random permutations. Discriminability was assessed by pair-wise contrasts of emotion maps. Consistent and discriminable activation patterns were observed for the five categories.

EmotionPeakRegions
HappinessRight superior temporal gyrus, left rostral anterior cingulate cortex.9 regional brain clusters.
SadnessLeft medial frontal gyrus.35 clusters – especially, left medial frontal gyrus, right middle temporal gyrus, and right inferior frontal gyrus.
AngerLeft inferior frontal gyrus.13 clusters – bilateral inferior frontal gyrus, and in right parahippocampal gyrus.
FearLeft amygdala.11 clusters – left amygdala and left putamen.
DisgustRight insula/right inferior frontal gyrus.16 clusters – right putamen and the left insula.

Lindquist et al. 2012

Lindquist, et al. reviewed 91 PET and fMRI studies published between January 1990 and December 2007. The studies used induction methods that elicit emotion experience or emotion perception of fear, sadness, disgust, anger, and happiness. The goal was to compare basic emotions approaches with psychological constructionist approaches. A MKDA transformed the individual peak into a neural reference space. The density analysis was then used to identify voxels with more consistent activations for a specific emotion category than all other emotions. Chi-squared analysis was used to create statistical maps that indicated whether each previously identified and consistently active region was more frequently activated in studies of each emotion category than average, regardless of activations elsewhere in the brain. Chi-squared analysis and density analysis both defined functionally consistent and selective regions (regions that showed a more consistent activity increase) for one emotion category. Thus, a selective region could present increased activations to multiple emotions, as long as the response to one emotion was relatively stronger.

A series of logistic regressions were performed to identify regions that while consistent and selective to an emotion were additionally specific to that emotion. Specificity was defined as showing increased activations for only one emotional category. Strong support for basic emotions was defined as evidence that brain areas respond to only one emotional category. Strong support for the constructionist approach was defined as evidence that psychological operations consistently occur across many brain regions and multiple emotional categories.

The results indicated that many brain regions demonstrated consistent and selective activations in the experience or perception of one emotion category. Consistent with constructionist models, however, no region demonstrated functional specificity for the emotions of fear, disgust, happiness, sadness or anger.

The authors proposed different roles for the brain regions that have traditionally been associated with only one emotion category. The authors propose that the amygdala, anterior insula, orbitofrontal cortex each contribute to “core affect,” which are basic feelings that are pleasant or unpleasant with some level of arousal.

RegionRole
AmygdalaIndicating whether external sensory information is motivationally salient, novel and/or evokes uncertainty.
Anterior InsulaRepresents core affective feelings in awareness across emotion categories, driven largely by body sensations.
Orbitofrontal CortexFunctions as a site for integrating sensory information from the body and the world to guide behaviour.

Closely related to core affect, the authors propose that the anterior cingulate and dorsolateral prefrontal cortex play vital roles in attention. The anterior cingulate supports the use of sensory information for directing attention and motor responses during response selection while the dorsolateral prefrontal cortex supporting executive attention. In many psychological construction approaches, emotions relate an individual’s situation in the world to internal body states, referred to as “conceptualisation”. The dorsomedial prefrontal cortex and hippocampus were consistently active in this context: regions that play an important role conceptualising are also involved in simulating previous experience (e.g. knowledge, memory). Language is also central to conceptualising, and regions that support language, including ventrolateral prefrontal cortex, were also consistently active across studies of emotion experience and perception.

What is Clinical Neuroscience?

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Introduction

Clinical neuroscience is a branch of neuroscience that focuses on the scientific study of fundamental mechanisms that underlie diseases and disorders of the brain and central nervous system.

It seeks to develop new ways of conceptualising and diagnosing such disorders and ultimately of developing novel treatments.

A clinical neuroscientist is a scientist who has specialised knowledge in the field. Not all clinicians are clinical neuroscientists. Clinicians and scientists – including psychiatrists, neurologists, clinical psychologists, neuroscientists, and other specialists – use basic research findings from neuroscience in general and clinical neuroscience in particular to develop diagnostic methods and ways to prevent and treat neurobiological disorders. Such disorders include addiction, Alzheimer’s disease, amyotrophic lateral sclerosis, anxiety disorders, attention deficit hyperactivity disorder, autism, bipolar disorder, brain tumours, depression, Down syndrome, dyslexia, epilepsy, Huntington’s disease, multiple sclerosis, neurological AIDS, neurological trauma, pain, obsessive-compulsive disorder, Parkinson’s disease, schizophrenia, sleep disorders, stroke and Tourette syndrome.

While neurology, neurosurgery and psychiatry are the main medical specialties that use neuroscientific information, other specialties such as cognitive neuroscience, neuroradiology, neuropathology, ophthalmology, otorhinolaryngology, anaesthesiology and rehabilitation medicine can contribute to the discipline. Integration of the neuroscience perspective alongside other traditions like psychotherapy, social psychiatry or social psychology will become increasingly important.

One Mind for Research

The “One Mind for Research” forum was a convention held in Boston, Massachusetts on 23 to 25 May 2011 that produced the blueprint document A Ten-Year Plan for Neuroscience: From Molecules to Brain Health. Leading neuroscience researchers and practitioners in the United States contributed to the creation of this document, in which 17 key areas of opportunities are listed under the Clinical Neuroscience section. These include the following:

  • Rethinking curricula to break down intellectual silos.
  • Training translational neuroscientists and clinical investigators.
  • Investigating biomarkers.
  • Improving psychiatric diagnosis.
  • Developing a “Framingham Study of Brain Disorders” (i.e. longitudinal cohort for central nervous system disease).
  • Identifying developmental risk factors and producing effective interventions.
  • Discovering new treatments for pain, including neuropathic pain.
  • Treating disorders of neural signalling and pathological synchrony.
  • Treating disorders of immunity or inflammation.
  • Treating metabolic and mitochondrial disorders.
  • Developing new treatments for depression.
  • Treating addictive disorders.
  • Improving treatment of schizophrenia.
  • Preventing and treating cerebrovascular disease.
  • Achieving personalized medicine.
  • Understanding shared mechanisms of neurodegeneration.
  • Advancing anaesthesia.

In particular, it advocates for better integrated and scientifically driven curricula for practitioners, and it recommends that such curricula be shared among neurologists, psychiatrists, psychologists, neurosurgeons and neuroradiologists.

Given the various ethical, legal and societal implications for healthcare practitioners arising from advances in neuroscience, the University of Pennsylvania inaugurated the Penn Conference on Clinical Neuroscience and Society in July 2011.

What is Neuropsychoanalysis?

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Introduction

Neuropsychoanalysis integrates both neuroscience and psychoanalysis, to create a balanced and equal study of the human mind.

This overarching approach began as advances in neuroscience lead to breakthroughs which held pertinent information for the field of psychoanalysis. Despite advantages for these fields to interconnect, there is some concern that too much emphasis on neurobiological physiology of the brain will undermine the importance of dialogue and exploration that is foundational to the field of psychoanalysis. Critics will also point to the qualitative and subjective nature of the field of psychoanalysis, claiming it cannot be fully reconciled with the quantitative and objective nature of neuroscientific research.

However, despite this critique, proponents of the field of neuropsychoanalysis remind critics that the father of psychoanalysis, Sigmund Freud himself, began his career as a neuroanatomist, further arguing that research in this category proves that the psychodynamic effects of the mind are inextricably linked to neural activity in the brain. Indeed, neuroscientific progress has created a shared study of many of the same cognitive phenomenon, and proponents for a distinct field under the heading of neuropsychoanalysis point to the ability for observation of both the subjective mind and empirical evidence in neurobiology to provide greater understanding and greater curative methods.

Therefore, neurospsychoanalysis aims to bring a field, often viewed as belonging more to the humanities than the sciences, into the scientific realm and under the umbrella of neuroscience, distinct from psychoanalysis, and yet adding to the plethora of insight garnered from it.

Brief History

Neuropsychoanalysis as a discipline can be traced as far back as Sigmund Freud’s manuscript, “Project for a Scientific Psychology”. Written in 1895, but only published posthumously, Freud developed his theories of the neurobiological function of the storage of memory in this work. His statement, based on his theory that memory is biologically stored in the brain by, “a permanent alteration following an event”, had a prophetic insight into the empirical discoveries that would corroborate these theories close to 100 years later. Freud speculated that psychodynamics and neurobiology would eventually reunite as one field of study. While time would eventually prove him correct to some degree, the latter half of the 20th century only saw a very gradual movement in this direction with only a few individuals championing this line of thought.

Significant advances in neuroscience throughout the 20th century created a clearer understanding of the functionality of the brain, which have vastly enhanced the way we view the mind. This began in the 1930s with the invention of electroencephalography, which enabled imaging of the brain as never seen before. A decade later the use of dynamic localisation, or the lesion method, further shed light onto the interaction of systems in the brain. Computerised tomography (CT) lead to even greater understanding of the interaction within the brain, and finally the invention of multiple scan technologies in the 1990s, the functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and the single photon emission computed tomography (SPECT) gave researchers empirical evidence of neurobiological processes.

It was in 1999, just before the turn of the century, that the term “neuropsychoanalysis” was used in a new journal entitled with the same name. This term once was hyphenated to indicate that the conjoining of the two fields of study did not suggest that they had been fully integrated, but rather that this new line of scientific inquiry was interdisciplinary. With repeated use, the hyphen was lost, and the name appears as we see it today.

Theoretical Base

Dual-Aspect Monism

Neuropsychoanalysis is best described as a marriage between neuroscience and psychoanalysis. However, its relationship to the broader field of neuropsychology – which relates the biological brain to psychological functions and behaviour – cannot be denied. Indeed, neuropsychoanalysis further seeks to remedy classical neurology’s exclusion of the subjective mind.

The subjective mind, that is, sensations, thoughts, feelings and consciousness, can seem antithetical to the cellular matter that makes up the neurobiology of the brain. Indeed, while Freud is most often credited with being the seminal creator of the study of the mind in modern terms, it was Descartes who concluded that mind and brain were two entirely different kinds of stuff. Accordingly, he invented the “dualism” of the mind, the mind-body dichotomy. Body is one kind of thing, and mind (or spirit or soul) is another. But since this second kind of stuff does not lend itself to scientific inquiry, many of today’s psychologists and neuroscientists have seemingly rejected Cartesian dualism.

Neuropsychoanalysis meets this challenge via dual-aspect monism, sometimes referred to as perspectivism. That is, we are monistic. Our brains, including mind, are made of one kind of stuff, cells, but we perceive this stuff in two different ways.

Psychoanalysis as a Foundation

Perhaps because Freud himself began his career as a neurologist, psychoanalysis has given the field of neuroscience the platform upon which many of its scientific hypotheses were founded. With the field of psychoanalysis suffering from what many see as a decline in innovation and popularity, a call for new approaches and a more scientific methodology is long overdue. The history of neuropsychoanalysis therefore, goes some way in explaining why some consider it the logical conclusion, and representative of an evolution that psychoanalysis was in need of. Since the mind itself is viewed as purely ontological, our appreciation of reality is dependent on neurobiological functions of the brain, which we can use to observe “subjectively,” from inside, how we feel and what we think. Freud refined this kind of observation into free association. He claimed and that this is the best technique that we have for perceiving complex mental functions that simple introspection will not reveal. Through psychoanalysis, we can discover mind’s unconscious functioning.

Neuroscience as a Foundation

Due to the very nature of neuropsychoanalysis, those working in this burgeoning field have been able to draw useful insights from a number of distinguished neuroscientists, indeed many of these now serve on the editorial board of the journal Neuropsychoanalysis. Some of these more notable names foundational to the development of neuropsychoanalysis include:

  • Antonio Damasio.
  • Eric Kandel.
  • Joseph LeDoux.
  • Helen Mayberg.
  • Jaak Panksepp.
  • VS Ramachandran.
  • Oliver Sacks.
  • Mark Solms.

Neuroscientists, often studying the same cognitive functions of the brain as psychoanalysts, do so in quantitative methods such as dissection post mortem, small lesions administered to create certain curative effects, or with the visual and objective aid of brain imaging, all of which enable researchers to trace neurochemical pathways and build a more accurate understanding of the physical functioning of the brain. Another branch of neuroscience also observes the “mind” from outside, that is, by means of neurological examination. This is often done in the form of physical tests, such as questionnaires, the Boston Naming test or Wisconsin Sorting, creating bisecting lines, acting out how one performs daily tasks such as a screwdriver, just to name a few. Neurologists can compare the changes in psychological function that the neurological examination shows with the associated changes in the brain, either post mortem or by means of modern imaging technology. Much of neuroscience aims to break down and tease out the cognitive and biological functions behind both conscious and unconscious actions within the brain. In this way it is no different than psychoanalysis, which has had similar goals since its inception. Therefore, to ignore the additional insight neuroscience can offer psychoanalysis would be to limit a huge source of knowledge that can only enhance psychoanalysis as a whole.

Models of Pathologies

Depression

Heinz Böker and Rainer Krähenman proposed a model depression as dysregulation of the relationship between the self and the other. This psychodynamic model, is related to the neurobiological model of the default mode network, DMN, and the executive network, EN, of the brain, noting experimentally the DMN seemed to be more active in depressed patients. The psychological construct of rumination is conceptualised which is experimentally more common in depressed patients, is viewed as equivalent to the cognitive processing of the self, and therefore the activation of the DMN. Similarly, experimentally measurable constructs of attribution bias are viewed as being related to this “cognitive processing of self”. It has been shown that forms of psychodynamic therapy for depression have effects on the activation of several areas of the brain.

Research Directions

Neuropsychoanalytic relate unconscious (and sometimes conscious) functioning discovered through the techniques of psychoanalysis or experimental psychology to underlying brain processes. Among the ideas explored in recent research are the following:

  • “Consciousness” is limited (5-9 bits of information) compared to emotional and unconscious thinking based in the limbic system.
    • Note: Solm’s book showed as reference in the footnote does not provide such an information.
    • It may be confused with the capacity of short-term memory.
  • Secondary-process, reality-oriented thinking can be understood as frontal lobe executive control systems.
  • Dreams, confabulations, and other expressions of primary-process thinking are meaningful, wish-fulfilling manifestations of the loss of frontal executive control of mesocortical and mesolimbic “seeking” systems.
  • Freud’s “libido” corresponds to a dopaminergic seeking system.
  • Drives can be understood as a series of basic emotions (prompts to action) anchored in pontine regions, specifically the periaqueductal gray, and projecting to cortex: play; seeking; caring; fear; anger; sadness. Seeking is constantly active; the others seek appropriate consummations (corresponding to Freud’s “dynamic” unconscious).
  • Seemingly rational and conscious decisions are driven from the limbic system by emotions which are unconscious.
  • Infantile amnesia (the absence of memory for the first years of life) occurs because the verbal left hemisphere becomes activated later, in the second or third year of life, after the non-verbal right hemisphere.
    • But infants can and do have procedural and emotional memories.
  • Infants’ first-year experiences of attachment and second-year (approximately) experiences of disapproval lay down pathways that regulate emotions and profoundly affect adult personality.
  • Oedipal behaviors (observable in primates) can be understood as the effort to integrate lust systems (testosterone-driven), romantic love (dopamine-driven), and attachment (oxytocin-driven) in relation to key persons in the environment.
  • Differences between the sexes are more biologically-based and less environmentally-driven than Freud believed.

Principles for Improving Investment in Translational Neuroscience Aimed at Psychiatric Drug Discovery

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Research Paper Title

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology.

Background

There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.

Methods

Based on a review of the relevant literature, the researchers formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.

Results

The researchers propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery:

  1. Consider incorporating the NIMH Research Domain Criteria (RDoC) approach;
  2. Engage the power of translational and systems neuroscience approaches;
  3. Use disease-relevant experimental perturbations;
  4. Identify molecular targets via genomic analysis and patient-derived pluripotent stem cells;
  5. Embrace holistic neuroscience: a partnership with psychoneuroimmunology;
  6. Use translational measures of neuronal activation;
  7. Validate the reproducibility of findings by independent collaboration; and
  8. Learn and reflect.

They provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities.

Conclusions: We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Reference

Tricklebank, M.D., Robbins, T.W., Simmons, C. & Wong, E.H.F. (2021) Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology. Psychopharmacology (Berl). doi: 10.1007/s00213-021-05787-x. Online ahead of print.

What is Neurodiversity?

Published on by Andrew Marshall1 Comment

Introduction

The term neurodiversity refers to variation in the human brain regarding sociability, learning, attention, mood and other mental functions.

It was coined in 1998 by sociologist Judy Singer, who helped popularise the concept along with journalist Harvey Blume. It emerged as a challenge to prevailing views that certain neurodevelopmental disorders are inherently pathological and instead adopts the social model of disability, in which societal barriers are the main contributing factor that disables people. This view is especially popular within the autism rights movement. The subsequent neurodiversity paradigm has been controversial among disability advocates, with opponents saying that its conceptualisation does not reflect the realities of individuals who have high support needs.

Brief History

The word neurodiversity is attributed to Judy Singer, a social scientist who has described herself as “likely somewhere on the autistic spectrum” and used the term in her sociology honours thesis published in 1999. The term represented a move away from previous “mother-blaming” theories about the cause of autism. Singer had been in correspondence with Blume as a result of their mutual interest in autism, and though he did not credit Singer, the word first appeared in print in an article by Blume in The Atlantic on 30 September 1998.

Some authors also credit the earlier work of autistic advocate Jim Sinclair in advancing the concept of neurodiversity. Sinclair was a principal early organiser of the international online autism community. Sinclair’s 1993 speech, “Don’t Mourn For Us”, emphasized autism as a way of being: “It is not possible to separate the person from the autism.” In a New York Times piece written by American journalist and writer Harvey Blume on 30 June 1997, Blume described the foundation of neurodiversity using the term “neurological pluralism”. Blume was an early advocate who predicted the role the Internet would play in fostering the international neurodiversity movement.

The term “neurodiversity” has since been applied to other conditions and has taken on a more general meaning; for example, the Developmental Adult Neurodiversity Association (DANDA) in the UK encompasses developmental coordination disorder, ADHD, Asperger’s syndrome, and related conditions.

Within Disability Rights Movements

The neurodiversity paradigm was taken up first by individuals on the autism spectrum. Subsequently, it was applied to other neurodevelopmental conditions such as ADHD, developmental speech disorders, dyslexia, dyspraxia, dyscalculia, dysnomia, intellectual disability and Tourette syndrome, as well as schizophrenia, and some mental health conditions such as bipolarity, schizoaffective disorder, antisocial personality disorder, dissociative disorders, and obsessive-compulsive disorder. Neurodiversity advocates denounce the framing of autism, ADHD, dyslexia, and other neurodevelopmental disorders as requiring medical intervention to “cure” or “fix” them, and instead promote support systems such as inclusion-focused services, accommodations, communication and assistive technologies, occupational training, and independent living support. The intention is for individuals to receive support that honours authentic forms of human diversity, self-expression, and being, rather than treatment which coerces or forces them to adopt normative ideas of normality, or to conform to a clinical ideal.

Proponents of neurodiversity strive to reconceptualize autism and related conditions in society by the following measures: acknowledging that neurodiversity does not require a cure; changing the language from the current “condition, disease, disorder, or illness”-based nomenclature and “broaden[ing] the understanding of healthy or independent living”; acknowledging new types of autonomy; and giving non-neurotypical individuals more control over their treatment, including the type, timing, and whether there should be treatment at all.

A 2009 study separated 27 students (with autism, dyslexia, developmental coordination disorder, ADHD, and stroke), into two categories of self-view: “a ‘difference’ view—where neurodiversity was seen as a difference incorporating a set of strengths and weaknesses, or a ‘medical/deficit’ view—where neurodiversity was seen as a disadvantageous medical condition.” They found that, although all of the students reported uniformly difficult schooling careers involving exclusion, abuse, and bullying, those who viewed themselves from a difference view (41% of the study cohort) “indicated higher academic self-esteem and confidence in their abilities and many (73%) expressed considerable career ambitions with positive and clear goals.” Many of these students reported gaining this view of themselves through contact with neurodiversity advocates in online support groups.

A 2013 online survey, which aimed to assess conceptions of autism and neurodiversity, found that “a deficit-as-difference conception of autism suggests the importance of harnessing autistic traits in developmentally beneficial ways, transcending a false dichotomy between celebrating differences and ameliorating deficit.”

Neurodiversity advocates point out that neurodiverse people often have exceptional abilities such as hyperfocus alongside their deficits. In particular, autistic people may have exceptional memory or even savant skills. In the autistic population, even those without savant skills are more likely than those in the general population to have exceptional knowledge or abilities in narrow domains.

Controversy

The neurodiversity paradigm is controversial in autism advocacy. The dominant paradigm is one which pathologizes human brains that diverge from those considered typical. From this perspective, these brains have medical conditions which should be treated.

A common criticism is that the neurodiversity paradigm is too widely encompassing and that its conception should exclude those whose functioning is more severely impaired. Autistic advocate and interdisciplinary educator Nick Walker offers the distinction that neurodivergencies refer specifically to “pervasive neurocognitive differences” that are “intimately related to the formation and constitution of the self,” in contrast to medical conditions such as epilepsy.

Neurodiversity advocate John Elder Robison agrees that neurological difference may sometimes produce disability, but at the same time he argues that the disability caused by neurological difference may be inseparable from the strengths it provides. “99 neurologically identical people fail to solve a problem, it’s often the 1% fellow who’s different who holds the key. Yet that person may be disabled or disadvantaged most or all of the time. To neurodiversity proponents, people are disabled because they are at the edges of the bell curve; not because they are sick or broken.” He therefore argues for the accommodation of neurological difference, while also recognising that it can produce disability.

What is Neuroscience?

Published on by Andrew Marshall3 Comments

Introduction

Neuroscience (or neurobiology) is the scientific study of the nervous system. It is a multidisciplinary science that combines physiology, anatomy, molecular biology, developmental biology, cytology, mathematical modelling, and psychology to understand the fundamental and emergent properties of neurons and neural circuits. The understanding of the biological basis of learning, memory, behaviour, perception, and consciousness has been described by Eric Kandel as the “ultimate challenge” of the biological sciences.

The scope of neuroscience has broadened over time to include different approaches used to study the nervous system at different scales and the techniques used by neuroscientists have expanded enormously, from molecular and cellular studies of individual neurons to imaging of sensory, motor and cognitive tasks in the brain.

Brief History

The earliest study of the nervous system dates to ancient Egypt. Trepanation, the surgical practice of either drilling or scraping a hole into the skull for the purpose of curing head injuries or mental disorders, or relieving cranial pressure, was first recorded during the Neolithic period. Manuscripts dating to 1700 BC indicate that the Egyptians had some knowledge about symptoms of brain damage.

Early views on the function of the brain regarded it to be a “cranial stuffing” of sorts. In Egypt, from the late Middle Kingdom onwards, the brain was regularly removed in preparation for mummification. It was believed at the time that the heart was the seat of intelligence. According to Herodotus, the first step of mummification was to “take a crooked piece of iron, and with it draw out the brain through the nostrils, thus getting rid of a portion, while the skull is cleared of the rest by rinsing with drugs.”

The view that the heart was the source of consciousness was not challenged until the time of the Greek physician Hippocrates. He believed that the brain was not only involved with sensation – since most specialised organs (e.g. eyes, ears, tongue) are located in the head near the brain – but was also the seat of intelligence. Plato also speculated that the brain was the seat of the rational part of the soul. Aristotle, however, believed the heart was the centre of intelligence and that the brain regulated the amount of heat from the heart. This view was generally accepted until the Roman physician Galen, a follower of Hippocrates and physician to Roman gladiators, observed that his patients lost their mental faculties when they had sustained damage to their brains.

Abulcasis, Averroes, Avicenna, Avenzoar, and Maimonides, active in the Medieval Muslim world, described a number of medical problems related to the brain. In Renaissance Europe, Vesalius (1514-1564), René Descartes (1596-1650), Thomas Willis (1621-1675) and Jan Swammerdam (1637-1680) also made several contributions to neuroscience.

Luigi Galvani’s pioneering work in the late 1700s set the stage for studying the electrical excitability of muscles and neurons. In the first half of the 19th century, Jean Pierre Flourens pioneered the experimental method of carrying out localised lesions of the brain in living animals describing their effects on motricity, sensibility and behaviour. In 1843 Emil du Bois-Reymond demonstrated the electrical nature of the nerve signal, whose speed Hermann von Helmholtz proceeded to measure, and in 1875 Richard Caton found electrical phenomena in the cerebral hemispheres of rabbits and monkeys. Adolf Beck published in 1890 similar observations of spontaneous electrical activity of the brain of rabbits and dogs. Studies of the brain became more sophisticated after the invention of the microscope and the development of a staining procedure by Camillo Golgi during the late 1890s. The procedure used a silver chromate salt to reveal the intricate structures of individual neurons. His technique was used by Santiago Ramón y Cajal and led to the formation of the neuron doctrine, the hypothesis that the functional unit of the brain is the neuron. Golgi and Ramón y Cajal shared the Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions, and categorizations of neurons throughout the brain.

In parallel with this research, work with brain-damaged patients by Paul Broca suggested that certain regions of the brain were responsible for certain functions. At the time, Broca’s findings were seen as a confirmation of Franz Joseph Gall’s theory that language was localised and that certain psychological functions were localised in specific areas of the cerebral cortex. The localisation of function hypothesis was supported by observations of epileptic patients conducted by John Hughlings Jackson, who correctly inferred the organisation of the motor cortex by watching the progression of seizures through the body. Carl Wernicke further developed the theory of the specialisation of specific brain structures in language comprehension and production. Modern research through neuroimaging techniques, still uses the Brodmann cerebral cytoarchitectonic map (referring to study of cell structure) anatomical definitions from this era in continuing to show that distinct areas of the cortex are activated in the execution of specific tasks.

During the 20th century, neuroscience began to be recognised as a distinct academic discipline in its own right, rather than as studies of the nervous system within other disciplines. Eric Kandel and collaborators have cited David Rioch, Francis O. Schmitt, and Stephen Kuffler as having played critical roles in establishing the field. Rioch originated the integration of basic anatomical and physiological research with clinical psychiatry at the Walter Reed Army Institute of Research, starting in the 1950s. During the same period, Schmitt established a neuroscience research programme within the Biology Department at the Massachusetts Institute of Technology, bringing together biology, chemistry, physics, and mathematics. The first freestanding neuroscience department (then called Psychobiology) was founded in 1964 at the University of California, Irvine by James L. McGaugh. This was followed by the Department of Neurobiology at Harvard Medical School, which was founded in 1966 by Stephen Kuffler.

The understanding of neurons and of nervous system function became increasingly precise and molecular during the 20th century. For example, in 1952, Alan Lloyd Hodgkin and Andrew Huxley presented a mathematical model for transmission of electrical signals in neurons of the giant axon of a squid, which they called “action potentials”, and how they are initiated and propagated, known as the Hodgkin-Huxley model. In 1961–1962, Richard FitzHugh and J. Nagumo simplified Hodgkin-Huxley, in what is called the FitzHugh-Nagumo model. In 1962, Bernard Katz modelled neurotransmission across the space between neurons known as synapses. Beginning in 1966, Eric Kandel and collaborators examined biochemical changes in neurons associated with learning and memory storage in Aplysia. In 1981 Catherine Morris and Harold Lecar combined these models in the Morris-Lecar model. Such increasingly quantitative work gave rise to numerous biological neuron models and models of neural computation.

As a result of the increasing interest about the nervous system, several prominent neuroscience organizations have been formed to provide a forum to all neuroscientist during the 20th century. For example, the International Brain Research Organisation was founded in 1961, the International Society for Neurochemistry in 1963, the European Brain and Behaviour Society in 1968, and the Society for Neuroscience in 1969. Recently, the application of neuroscience research results has also given rise to applied disciplines as neuroeconomics, neuroeducation, neuroethics, and neurolaw.

Over time, brain research has gone through philosophical, experimental, and theoretical phases, with work on brain simulation predicted to be important in the future.

Modern Neuroscience

The scientific study of the nervous system increased significantly during the second half of the twentieth century, principally due to advances in molecular biology, electrophysiology, and computational neuroscience. This has allowed neuroscientists to study the nervous system in all its aspects: how it is structured, how it works, how it develops, how it malfunctions, and how it can be changed.

For example, it has become possible to understand, in much detail, the complex processes occurring within a single neuron. Neurons are cells specialised for communication. They are able to communicate with neurons and other cell types through specialised junctions called synapses, at which electrical or electrochemical signals can be transmitted from one cell to another. Many neurons extrude a long thin filament of axoplasm called an axon, which may extend to distant parts of the body and are capable of rapidly carrying electrical signals, influencing the activity of other neurons, muscles, or glands at their termination points. A nervous system emerges from the assemblage of neurons that are connected to each other.

The vertebrate nervous system can be split into two parts: the central nervous system (defined as the brain and spinal cord), and the peripheral nervous system. In many species – including all vertebrates – the nervous system is the most complex organ system in the body, with most of the complexity residing in the brain. The human brain alone contains around one hundred billion neurons and one hundred trillion synapses; it consists of thousands of distinguishable substructures, connected to each other in synaptic networks whose intricacies have only begun to be unravelled. At least one out of three of the approximately 20,000 genes belonging to the human genome is expressed mainly in the brain.

Due to the high degree of plasticity of the human brain, the structure of its synapses and their resulting functions change throughout life.

Making sense of the nervous system’s dynamic complexity is a formidable research challenge. Ultimately, neuroscientists would like to understand every aspect of the nervous system, including how it works, how it develops, how it malfunctions, and how it can be altered or repaired. Analysis of the nervous system is therefore performed at multiple levels, ranging from the molecular and cellular levels to the systems and cognitive levels. The specific topics that form the main foci of research change over time, driven by an ever-expanding base of knowledge and the availability of increasingly sophisticated technical methods. Improvements in technology have been the primary drivers of progress. Developments in electron microscopy, computer science, electronics, functional neuroimaging, and genetics and genomics have all been major drivers of progress.

Molecular and Cellular Neuroscience

Basic questions addressed in molecular neuroscience include the mechanisms by which neurons express and respond to molecular signals and how axons form complex connectivity patterns. At this level, tools from molecular biology and genetics are used to understand how neurons develop and how genetic changes affect biological functions. The morphology, molecular identity, and physiological characteristics of neurons and how they relate to different types of behaviour are also of considerable interest.

Questions addressed in cellular neuroscience include the mechanisms of how neurons process signals physiologically and electrochemically. These questions include how signals are processed by neurites and somas and how neurotransmitters and electrical signals are used to process information in a neuron. Neurites are thin extensions from a neuronal cell body, consisting of dendrites (specialised to receive synaptic inputs from other neurons) and axons (specialised to conduct nerve impulses called action potentials). Somas are the cell bodies of the neurons and contain the nucleus.

Another major area of cellular neuroscience is the investigation of the development of the nervous system. Questions include the patterning and regionalisation of the nervous system, neural stem cells, differentiation of neurons and glia (neurogenesis and gliogenesis), neuronal migration, axonal and dendritic development, trophic interactions, and synapse formation.

Computational neurogenetic modelling is concerned with the development of dynamic neuronal models for modelling brain functions with respect to genes and dynamic interactions between genes.

Neural Circuits and Systems

Questions in systems neuroscience include how neural circuits are formed and used anatomically and physiologically to produce functions such as reflexes, multisensory integration, motor coordination, circadian rhythms, emotional responses, learning, and memory. In other words, they address how these neural circuits function in large-scale brain networks, and the mechanisms through which behaviours are generated. For example, systems level analysis addresses questions concerning specific sensory and motor modalities: how does vision work? How do songbirds learn new songs and bats localize with ultrasound? How does the somatosensory system process tactile information? The related fields of neuroethology and neuropsychology address the question of how neural substrates underlie specific animal and human behaviours. Neuroendocrinology and psychoneuroimmunology examine interactions between the nervous system and the endocrine and immune systems, respectively. Despite many advancements, the way that networks of neurons perform complex cognitive processes and behaviours is still poorly understood.

Cognitive and Behavioural Neuroscience

Cognitive neuroscience addresses the questions of how psychological functions are produced by neural circuitry. The emergence of powerful new measurement techniques such as neuroimaging (e.g. fMRI, PET, SPECT), EEG, MEG, electrophysiology, optogenetics and human genetic analysis combined with sophisticated experimental techniques from cognitive psychology allows neuroscientists and psychologists to address abstract questions such as how cognition and emotion are mapped to specific neural substrates. Although many studies still hold a reductionist stance looking for the neurobiological basis of cognitive phenomena, recent research shows that there is an interesting interplay between neuroscientific findings and conceptual research, soliciting and integrating both perspectives. For example, neuroscience research on empathy solicited an interesting interdisciplinary debate involving philosophy, psychology and psychopathology. Moreover, the neuroscientific identification of multiple memory systems related to different brain areas has challenged the idea of memory as a literal reproduction of the past, supporting a view of memory as a generative, constructive and dynamic process.

Neuroscience is also allied with the social and behavioural sciences as well as nascent interdisciplinary fields such as neuroeconomics, decision theory, social neuroscience, and neuromarketing to address complex questions about interactions of the brain with its environment. A study into consumer responses for example uses EEG to investigate neural correlates associated with narrative transportation into stories about energy efficiency.

Computational Neuroscience

Questions in computational neuroscience can span a wide range of levels of traditional analysis, such as development, structure, and cognitive functions of the brain. Research in this field utilises mathematical models, theoretical analysis, and computer simulation to describe and verify biologically plausible neurons and nervous systems. For example, biological neuron models are mathematical descriptions of spiking neurons which can be used to describe both the behaviour of single neurons as well as the dynamics of neural networks. Computational neuroscience is often referred to as theoretical neuroscience.

Nanoparticles in medicine are versatile in treating neurological disorders showing promising results in mediating drug transport across the blood brain barrier. Implementing nanoparticles in antiepileptic drugs enhances their medical efficacy by increasing bioavailability in the bloodstream, as well as offering a measure of control in release time concentration. Although nanoparticles can assist therapeutic drugs by adjusting physical properties to achieve desirable effects, inadvertent increases in toxicity often occur in preliminary drug trials. Furthermore, production of nanomedicine for drug trials is economically consuming, hindering progress in their implementation. Computational models in nanoneuroscience provide alternatives to study the efficacy of nanotechnology-based medicines in neurological disorders while mitigating potential side effects and development costs.

Nanomaterials often operate at length scales between classical and quantum regimes. Due to the associated uncertainties at the length scales that nanomaterials operate, it is difficult to predict their behaviour prior to in vivo studies. Classically, the physical processes which occur throughout neurons are analogous to electrical circuits. Designers focus on such analogies and model brain activity as a neural circuit. Success in computational modelling of neurons have led to the development of stereochemical models that accurately predict acetylcholine receptor-based synapses operating at microsecond time scales.

Ultrafine nanoneedles for cellular manipulations are thinner than the smallest single walled carbon nanotubes. Computational quantum chemistry is used to design ultrafine nanomaterials with highly symmetrical structures to optimise geometry, reactivity and stability.

Behaviour of nanomaterials are dominated by long ranged non-bonding interactions. Electrochemical processes that occur throughout the brain generate an electric field which can inadvertently affect the behaviour of some nanomaterials. Molecular dynamics simulations can mitigate the development phase of nanomaterials as well as prevent neural toxicity of nanomaterials following in vivo clinical trials. Testing nanomaterials using molecular dynamics optimizes nano characteristics for therapeutic purposes by testing different environment conditions, nanomaterial shape fabrications, nanomaterial surface properties, etc without the need for in vivo experimentation. Flexibility in molecular dynamic simulations allows medical practitioners to personalise treatment. Nanoparticle related data from translational nanoinformatics links neurological patient specific data to predict treatment response.

Nano-Neurotechnology

The visualization of neuronal activity is of key importance in the study of neurology. Nano-imaging tools with nanoscale resolution help in these areas. These optical imaging tools are PALM and STORM which helps visualise nanoscale objects within cells. Pampaloni states that, so far, these imaging tools revealed the dynamic behaviour and organisation of the actin cytoskeleton inside the cells, which will assist in understanding how neurons probe their involvement during neuronal outgrowth and in response to injury, and how they differentiate axonal processes and characterisation of receptor clustering and stoichiometry at the plasma inside the synapses, which are critical for understanding how synapses respond to changes in neuronal activity. These past works focused on devices for stimulation or inhibition of neural activity, but the crucial aspect is the ability for the device to simultaneously monitor neural activity. The major aspect that is to be improved in the nano imaging tools is the effective collection of the light as a major problem is that biological tissue are dispersive media that do not allow a straightforward propagation and control of light. These devices use nanoneedle and nanowire (NWs) for probing and stimulation.

NWs are artificial nano- or micro-sized “needles” that can provide high-fidelity electrophysiological recordings if used as microscopic electrodes for neuronal recordings. NWs are an attractive as they are highly functional structures that offer unique electronic properties that are affected by biological/chemical species adsorbed on their surface; mostly the conductivity. This conductivity variance depending on chemical species present allows enhanced sensing performances. NWs are also able to act as non-invasive and highly local probes. These versatility of NWs makes it optimal for interfacing with neurons due to the fact that the contact length along the axon (or the dendrite projection crossing a NW) is just about 20 nm.

Neuroscience and Medicine

Neurology, psychiatry, neurosurgery, psychosurgery, anesthesiology and pain medicine, neuropathology, neuroradiology, ophthalmology, otolaryngology, clinical neurophysiology, addiction medicine, and sleep medicine are some medical specialties that specifically address the diseases of the nervous system. These terms also refer to clinical disciplines involving diagnosis and treatment of these diseases.

Neurology works with diseases of the central and peripheral nervous systems, such as amyotrophic lateral sclerosis (ALS) and stroke, and their medical treatment. Psychiatry focuses on affective, behavioural, cognitive, and perceptual disorders. Anaesthesiology focuses on perception of pain, and pharmacologic alteration of consciousness. Neuropathology focuses upon the classification and underlying pathogenic mechanisms of central and peripheral nervous system and muscle diseases, with an emphasis on morphologic, microscopic, and chemically observable alterations. Neurosurgery and psychosurgery work primarily with surgical treatment of diseases of the central and peripheral nervous systems.

Translational Research

Recently, the boundaries between various specialties have blurred, as they are all influenced by basic research in neuroscience. For example, brain imaging enables objective biological insight into mental illnesses, which can lead to faster diagnosis, more accurate prognosis, and improved monitoring of patient progress over time.

Integrative neuroscience describes the effort to combine models and information from multiple levels of research to develop a coherent model of the nervous system. For example, brain imaging coupled with physiological numerical models and theories of fundamental mechanisms may shed light on psychiatric disorders.

Nanoneuroscience

One of the main goals of nanoneuroscience is to gain a detailed understanding of how the nervous system operates and, thus, how neurons organise themselves in the brain. Consequently, creating drugs and devices that are able to cross the blood brain barrier (BBB) are essential to allow for detailed imaging and diagnoses. The blood brain barrier functions as a highly specialised semipermeable membrane surrounding the brain, preventing harmful molecules that may be dissolved in the circulation blood from entering the central nervous system.

The main two hurdles for drug-delivering molecules to access the brain are size (must have a molecular weight < 400 Da) and lipid solubility. Physicians hope to circumvent difficulties in accessing the central nervous system through viral gene therapy. This often involves direct injection into the patient’s brain or cerebral spinal fluid. The drawback of this therapy is that it is invasive and carries a high risk factor due to the necessity of surgery for the treatment to be administered. Because of this, only 3.6% of clinical trials in this field have progressed to stage III since the concept of gene therapy was developed in the 1980s.

Another proposed way to cross the BBB is through temporary intentional disruption of the barrier. This method was first inspired by certain pathological conditions that were discovered to break down this barrier by themselves, such as Alzheimer’s disease, Parkinson’s disease, stroke, and seizure conditions.

Nanoparticles are unique from macromolecules because their surface properties are dependent on their size, allowing for strategic manipulation of these properties (or, “programming”) by scientists that would not be possible otherwise. Likewise, nanoparticle shape can also be varied to give a different set of characteristics based on the surface area to volume ratio of the particle.

Nanoparticles have promising therapeutic effects when treating neurodegenerative diseases. Oxygen reactive polymer (ORP) is a nano-platform programmed to react with oxygen and has been shown to detect and reduce the presence of reactive oxygen species (ROS) formed immediately after traumatic brain injuries. Nanoparticles have also been employed as a “neuroprotective” measure, as is the case with Alzheimer’s disease and stroke models. Alzheimer’s disease results in toxic aggregates of the amyloid beta protein formed in the brain. In one study, gold nanoparticles were programmed to attach themselves to these aggregates and were successful in breaking them up. Likewise, with ischemic stroke models, cells in the affected region of the brain undergo apoptosis, dramatically reducing blood flow to important parts of the brain and often resulting in death or severe mental and physical changes. Platinum nanoparticles have been shown to act as ROS, serving as “biological antioxidants” and significantly reducing oxidation in the brain as a result of stroke. Nanoparticles can also lead to neurotoxicity and cause permanent BBB damage either from brain oedema or from unrelated molecules crossing the BBB and causing brain damage. This proves further long term in vivo studies are needed to gain enough understanding to allow for successful clinical trials.

One of the most common nano-based drug delivery platforms is liposome-based delivery. They are both lipid-soluble and nano-scale and thus are permitted through a fully functioning BBB. Additionally, lipids themselves are biological molecules, making them highly biocompatible, which in turn lowers the risk of cell toxicity. The bilayer that is formed allows the molecule to fully encapsulate any drug, protecting it while it is travelling through the body. One drawback to shielding the drug from the outside cells is that it no longer has specificity, and requires coupling to extra antibodies to be able to target a biological site. Due to their low stability, liposome-based nanoparticles for drug delivery have a short shelf life.

Targeted therapy using magnetic nanoparticles (MNPs) is also a popular topic of research and has led to several stage III clinical trials. Invasiveness is not an issue here because a magnetic force can be applied from the outside of a patient’s body to interact and direct the MNPs. This strategy has been proven successful in delivering Brain-derived neurotropic factor, a naturally occurring gene thought to promote neurorehabilitation, across the BBB.

Major Branches

Modern neuroscience education and research activities can be very roughly categorised into the following major branches, based on the subject and scale of the system in examination as well as distinct experimental or curricular approaches. Individual neuroscientists, however, often work on questions that span several distinct subfields.

BranchDescription
Affective NeuroscienceAffective neuroscience is the study of the neural mechanisms involved in emotion, typically through experimentation on animal models.
Behavioural NeuroscienceBehavioural neuroscience (also known as biological psychology, physiological psychology, biopsychology, or psychobiology) is the application of the principles of biology to the study of genetic, physiological, and developmental mechanisms of behaviour in humans and non-human animals.
Cellular NeuroscienceCellular neuroscience is the study of neurons at a cellular level including morphology and physiological properties.
Clinical NeuroscienceThe scientific study of the biological mechanisms that underlie the disorders and diseases of the nervous system.
Cognitive NeuroscienceCognitive neuroscience is the study of the biological mechanisms underlying cognition.
Computational NeuroscienceComputational neuroscience is the theoretical study of the nervous system.
Cultural NeuroscienceCultural neuroscience is the study of how cultural values, practices and beliefs shape and are shaped by the mind, brain and genes across multiple timescales.
Developmental NeuroscienceDevelopmental neuroscience studies the processes that generate, shape, and reshape the nervous system and seeks to describe the cellular basis of neural development to address underlying mechanisms.
Evolutionary NeuroscienceEvolutionary neuroscience studies the evolution of nervous systems.
Molecular NeuroscienceMolecular neuroscience studies the nervous system with molecular biology, molecular genetics, protein chemistry, and related methodologies.
Neural NeuroscienceNeural engineering uses engineering techniques to interact with, understand, repair, replace, or enhance neural systems.
NeuroanatomyNeuroanatomy is the study of the anatomy of nervous systems.
NeurochemistryNeurochemistry is the study of how neurochemicals interact and influence the function of neurons.
NeuroethologyNeuroethology is the study of the neural basis of non-human animals behaviour.
NeurogastronomyNeurogastronomy is the study of flavour and how it affects sensation, cognition, and memory.
NeurogeneticsNeurogenetics is the study of the genetical basis of the development and function of the nervous system.
NeuroimagingNeuroimaging includes the use of various techniques to either directly or indirectly image the structure and function of the brain.
NeuroimmunologyNeuroimmunology is concerned with the interactions between the nervous and the immune system.
NeuroinformaticsNeuroinformatics is a discipline within bioinformatics that conducts the organisation of neuroscience data and application of computational models and analytical tools.
NeurolinguisticsNeurolinguistics is the study of the neural mechanisms in the human brain that control the comprehension, production, and acquisition of language.
NeurophysicsNeurophysics deals with the development of physical experimental tools to gain information about the brain.
NeurophysiologyNeurophysiology is the study of the functioning of the nervous system, generally using physiological techniques that include measurement and stimulation with electrodes or optically with ion- or voltage-sensitive dyes or light-sensitive channels.
NeuropsychologyNeuropsychology is a discipline that resides under the umbrellas of both psychology and neuroscience, and is involved in activities in the arenas of both basic science and applied science. In psychology, it is most closely associated with biopsychology, clinical psychology, cognitive psychology, and developmental psychology. In neuroscience, it is most closely associated with the cognitive, behavioural, social, and affective neuroscience areas. In the applied and medical domain, it is related to neurology and psychiatry.
PaleoneurobiologyPaleoneurobiology is a field which combines techniques used in palaeontology and archaeology to study brain evolution, especially that of the human brain.
Social NeuroscienceSocial neuroscience is an interdisciplinary field devoted to understanding how biological systems implement social processes and behaviour, and to using biological concepts and methods to inform and refine theories of social processes and behaviour.
Systems NeuroscienceSystems neuroscience is the study of the function of neural circuits and systems.

Neuroscience Organisations

The largest professional neuroscience organisation is the Society for Neuroscience (SFN), which is based in the United States but includes many members from other countries. Since its founding in 1969 the SFN has grown steadily: as of 2010 it recorded 40,290 members from 83 different countries. Annual meetings, held each year in a different American city, draw attendance from researchers, postdoctoral fellows, graduate students, and undergraduates, as well as educational institutions, funding agencies, publishers, and hundreds of businesses that supply products used in research.

Other major organisations devoted to neuroscience include the International Brain Research Organisation (IBRO), which holds its meetings in a country from a different part of the world each year, and the Federation of European Neuroscience Societies (FENS), which holds a meeting in a different European city every two years. FENS comprises a set of 32 national-level organisations, including the British Neuroscience Association, the German Neuroscience Society (Neurowissenschaftliche Gesellschaft), and the French Société des Neurosciences. The first National Honour Society in Neuroscience, Nu Rho Psi, was founded in 2006. Numerous youth neuroscience societies which support undergraduates, graduates and early career researchers also exist, like Project Encephalon.

In 2013, the BRAIN Initiative was announced in the US. An International Brain Initiative was created in 2017, currently integrated by more than seven national-level brain research initiatives (US, Europe, Allen Institute, Japan, China, Australia, Canada, Korea, Israel) spanning four continents.

Public Education and Outreach

In addition to conducting traditional research in laboratory settings, neuroscientists have also been involved in the promotion of awareness and knowledge about the nervous system among the general public and government officials. Such promotions have been done by both individual neuroscientists and large organisations. For example, individual neuroscientists have promoted neuroscience education among young students by organising the International Brain Bee, which is an academic competition for high school or secondary school students worldwide. In the United States, large organisations such as the Society for Neuroscience have promoted neuroscience education by developing a primer called Brain Facts, collaborating with public school teachers to develop Neuroscience Core Concepts for K-12 teachers and students, and cosponsoring a campaign with the Dana Foundation called Brain Awareness Week to increase public awareness about the progress and benefits of brain research. In Canada, the CIHR Canadian National Brain Bee is held annually at McMaster University.

Neuroscience educators formed Faculty for Undergraduate Neuroscience (FUN) in 1992 to share best practices and provide travel awards for undergraduates presenting at Society for Neuroscience meetings.

Finally, neuroscientists have also collaborated with other education experts to study and refine educational techniques to optimise learning among students, an emerging field called educational neuroscience. Federal agencies in the United States, such as the National Institute of Health (NIH) and National Science Foundation (NSF), have also funded research that pertains to best practices in teaching and learning of neuroscience concepts.