Join the collective network of neurologists, neuroscientists, and allied specialty professionals to create a research environment that tackled problems of global neurology.

Orla Hilton

By Dr. Orla Hilton

Founded in 2020, the Global Neuro Research Coalition works to advance research in global brain health and improve patient care through an ever-expanding international network of clinicians, allied health care workers, scientists, and policymakers who are passionate about brain health.

COVID-19 was the initial catalyst for the founding of the then-called Global COVID-19 Neuro Research Coalition, as the global neurological community began to be confronted with the largely unknown effects of SARS-CoV-2 on the nervous system and the inequalities in the management of patients who developed neurological complications of the virus. We have now expanded our focus and established as the Global Neuro Research Coalition, comprising over 120 members from 38 countries, with skills and translational expertise spanning from basic neuroscience research to clinical neurology and guidelines/policy decision-making.

Our coalition invites and welcomes new members of the global neurological community to join our collective network of neurologists, neuroscientists, and allied specialty professionals to create an inclusive research environment that can better understand and tackle the ever-evolving problems the field of global neurology faces.

Our mission statement: Advancing brain health research through interdisciplinary global collaboration.

The five pillars of the World Health Organization’s (WHO) Intersectoral Global Action Plan (IGAP) on Epilepsy and Other Neurological Disorders lie at the heart of our mission, as we work to harmonize networks and strategies for future neurological research and to develop clinical guidance by establishing open lines of communication between international colleagues and institutions, especially in low- and middle-income countries (LMICs).

The building and strengthening of such a coalition remain vital as we investigate and understand the long-term neurological and cognitive sequelae of COVID-19, and look forward to pursuing the translation of current and future neurological research into policies that promote a ‘one health’ approach.

To date, the coalition has published over 10 papers together. A key example of the power of our consortium to perform global neurological research is the International Inter-observer Variability Study by Tamborska et al. (Journal of the Neurological Sciences, 2023), undertaken in collaboration with the World Federation of Neurology. This brought together 146 researchers and clinicians from 45 countries, who looked at the diagnostic accuracy for the acute neurological complications of COVID-19 and demonstrated the need for training in the global reporting of neurological syndromes. Other key works of our coalition have addressed the neurological manifestations of acute COVID-19 infections. Examples include the Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients’ by Michael et al. (The Journal of Neuropsychiatry and Clinical Neurosciences, 2023), in addition Neurological Events Reported after COVID-19 Vaccines by Frontera et al. (Annals of Neurology, 2022), and Evaluation and Treatment Approaches for Neurological Post-Acute Sequelae of COVID-19 by Frontera et al. (Journal of the Neurological Sciences, 2023).

In addition, our coalition has also led to the creation of the Global Brain Health Clinical Exchange Platform in collaboration with the WHO. This platform hosts monthly free, online sessions, engaging hundreds of participants from over 50 countries to hear the latest from world leaders in neurology and exchange experience on the current challenges and future directions of a wide spectrum of neurological research. Topics have included the neuroepidemiology of emerging pathogens, management of acute neurological presentations, patient-and-public engagement and long-term care, and the delivery of improvements in health care systems.

The coalition is grateful for the ongoing support of the World Federation of Neurology and our other partner institutions. We endeavor to continue to collaborate and partner in an interdisciplinary way with other medical and allied specialties, especially in LMICs which often carry the heaviest burden of neurological disease. We welcome all new members. If you are interested in becoming part of the coalition, please visit https://www.liverpool.ac.uk/neurosciences-research-unit/knowledge-exchange/global-neuro-research-coalition/ and/or send an email to covidcns@liverpool.ac.uk. •

Dr. Orla Hilton (UK) is an academic foundation doctor in infectious diseases and clinical researcher for the national COVID-19 Clinical Neuroscience Study based at Infection Neuroscience Lab in Liverpool, UK.

A useful genetic data repository for clinical neurologists.

Foreward by Martin Krenn, Department of Neurology, Medical University, Vienna, Austria

A large number of neurological disorders are characterized by a strong genetic component, either in a monogenic or a more complex polygenic sense. This is illustrated by the extensive portion of the human genome actively expressed in the central and peripheral nervous systems. Over the past decade, new genome-wide sequencing technologies have enabled us to identify single-gene etiologies in an increasing number of cases. More recently, these methods have also entered clinical routine diagnostics. As most of these conditions are very rare, the utilization of publicly available genetic databases is of utmost relevance for clinical neurologists to better understand human gene-disease relationships in neurogenetic disorders.

The Online Mendelian Inheritance in Man (OMIM) database offers a widely used, comprehensive, and constantly updated compendium of a vast number of monogenic (Mendelian) conditions. It is based on the most recent biomedical literature and thus constitutes a particularly useful resource for clinicians, often referenced in genetic diagnostic reports. It can be expected that the clinical value of such repositories will further increase in the coming years, as new neurogenetic disorders are still being discovered at a rapid pace, and more targeted treatments for patients are being developed.

The Online Mendelian Inheritance in Man

Cassandra Kniffin Arnold and Joanna Amberger

In 1863, Nikolaus Friedreich described a juvenile-onset form of hereditary ataxia (Friedreich ataxia). Several years later, George Huntington described an adult-onset hereditary chorea (Huntington disease). Nearly 100 years later, these familial genetic neurologic disorders, along with over 1,400 other genetic disorders, were included in Dr. Victor McKusick’s seminal textbook Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes (MIM). These catalogs were updated and published regularly, and in 1987, MIM was made freely available and searchable online as OMIM^TM. Today, www.OMIM.org is a continuously updated, freely available compendium containing over 27,000 structured descriptions of human genetic disorders and genes. Currently, OMIM describes over 7,400 disorders caused by pathogenic variants in over 4,800 genes. On average, over 35,000 clinicians and researchers worldwide use OMIM daily to assist in disease gene discovery, clinical diagnosis, and management of genetic diseases, as well to understand the molecular bases of disease and the underlying medical science.

The information in OMIM is based on the peer-reviewed biomedical literature. Priority for inclusion in the database is given to published papers that provide significant insight into the phenotype-genotype relationship, expand our understanding of human biology, or contribute to the characterization of a genetic disorder.

Each OMIM entry (phenotype or gene) has a preferred title, with alternative names if relevant, and is given a unique 6-digit number that remains stable, even if the name changes. These OMIM accession numbers are used widely in publications and databases. OMIM entries are text-based and organized into consistent headings. Gene entries include information on gene structure, expression, function, animal models, and allelic variants, when available. Phenotype (disorder) entries include information on clinical features, inheritance, pathogenesis, genotype-phenotype correlations, and molecular genetics. In addition, each phenotype entry has an accompanying Clinical Synopsis, a concise tabular anatomical listing of the clinical features described in patients with the disorder. The relationship between phenotypes and genes is summarized in OMIM’s tabular Gene Map.

From its inception, MIM has played a foundational role in the nosology and naming of genetic disease.

In general, the naming and classification of disorders (phenotypes) in OMIM reflect that used in the respective medical community or as designated in the published paper(s).

OMIM curators evaluate reports of new phenotypes in the context of those present in the catalog and consider the following questions.

• How many patients have been described in how many reports?
• What shared features actually define the phenotype, and how thorough are the clinical descriptions?
• Does this constellation of features represent a new entity?
• Do the different features of a disorder constitute clinical variability of a single disorder or define separate disorders?
• Have the same or similar features been described under a different name?
• Is the phenotype similar to others in OMIM?
• Can the phenotype be classified with any other disorders?

Answering these questions must also take into account the views and possible disagreements in the genetics community as well as published nosologies. Since the definition of a phenotype (constellation of features) as a genetic entity is an evolving process, the names of a disorder in OMIM may change over time, but an OMIM number remains stable. Disease names should be unique, enhance clinical care and classification, and be easy to communicate. Acronyms and eponyms can both serve in this capacity, although eponyms should be used sparingly. When disease names, designations, and classification schemes are not provided in the papers or are not agreed upon in the medical community, the process of disease naming and classification involves defining recognizable patterns of features and highlighting those that allow one condition to be distinguished from another. For new disorders, the three to five most clinically significant features are selected to create an acronym or initialism that is both informative and memorable. It may seem appealing to name a genetic disorder after a gene; however, this is not recommended for several reasons. Patients present with clinical features, and not all phenotypes have a recognized molecular basis. Importantly, many people around the world will not be sequenced and their conditions should be catalogued. Additionally, one-third of disease genes cause more than one phenotype, each with its own unique features, prognosis, molecular pathogenesis, and treatment. Phenotypes and genes are distinct concepts, and their names should change appropriately and independently to reflect greater knowledge. The OMIM number unifies clinical names and aliases under a single identifier.

If the same or similar phenotype exists in OMIM but that phenotype is caused by variants in a different gene, the existing name is used and a serial number is added at the end. These genetically heterogeneous phenotypes are then assembled into “Phenotypic Series” and given a unique PS accession number. Grouping similar phenotypes using clinical naming provides unique insights into molecular mechanisms and disease etiology, and offers a broader context for understanding the complexity of similar diseases. Examples of genetically heterogeneous neurologic disorders include Charcot-Marie-Tooth disease (CMT, PS118220), hereditary spastic paraplegia (SPG/HSP, PS303350), spinocerebellar ataxia (SCA, PS164400), and developmental and epileptic encephalopathy (DEE, PS308350). The clinical synopses of members in a Phenotypic Series can be viewed side-by-side on the website; such a view reveals differences that can guide physicians toward the right diagnosis and management or treatment. Each Phenotypic Series sheds light on shared molecular pathology and mechanisms of disease and/or can reveal new divergent avenues of investigation.

OMIM.org is freely accessible and is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. The entries have copious directed links to external resources including DNA and protein databases (GenBank, Ensembl, UniProt), clinical resources (genetic testing sites, ClinGen, Orphanet), genetic variant resources, (ClinVar, gnomAD), and animal model databases (Mouse Genome Informatics, OMIA). OMIM supports programmatic access to its content via an API (Application Programming Interface). Also available from OMIM.org is the service MIMmatch. MIMmatch is a way for a user to follow OMIM entries of interest and to find other researchers who may share interest in the same topics. Registered MIMmatch users are able to receive alerts about updates to genes and diseases of interest and/or receive notification of new phenotype-gene relationships added to OMIM. Help in using OMIM.org is available from the website with both written guides and short video tutorials.

For over 55 years, OMIM has chronicled the collected knowledge of the field of medical genetics and remains one of the primary repositories of curated information on both genetic disorders (phenotypes) and genes and the relationships between them. •

Cassandra Kniffin Arnold, MD, is senior medical writer, and Joanna Amberger is program manager at OMIM, Johns Hopkins University in Baltimore, Maryland. Dr. Martin Krenn, PhD, is from the Department of Neurology, Medical University of Vienna in Austria.

Toward a pharmacology and toxicology of words.

Placebo and recently the term nocebo are often used in situations where uncertain effects, possibly the effect of the mind works, and have been often disregarded as scientifical activities. All of us working with patients are implicitly using the concept of placebo, and sometimes the negative prediction, the nocebo.

As members of the health profession, we are part of placebo effect, and investigations have shown that also in regular approved and effective drugs a percentage of placebo effect can be calculated. The awareness of these important effects are important. The perception of placebo effect can in several instances be blocked or denied by cultural practices, and for neurology, it is important to spread and enhance the global perception.

Prof. Benedetti has worked on the placebo effect over many years and has given the placebo effect a rational and scientific background.

We are pleased that Prof. Benedetti has accepted our invitation and given a short summary of his important work.

– Wolfgang Grisold

Fabrizio Benedetti, MD, MAE

Fabrizio Benedetti, MD, MAE

Modern medicine and neurology have progressed in parallel with the advancement of biochemistry, anatomy, and physiology. By using the tools of modern medicine and neurology, today the physician and the neurologist can treat and prevent a number of diseases through pharmacology, genetics, and physical interventions, including surgery. In addition to this materia medica, the patient’s mind, cognitions and emotions play a central part as well in any therapeutic outcome. Placebo effects are at the very heart of these issues and, maybe paradoxically, they can be approached by using the same biochemical, cellular, and physiological tools of the materia medica, which represents an epochal transition from general concepts such as suggestibility and power of mind to a true physiology and biology.

Placebo effects remind us of the old tenet that patients must be both cured and cared for, and they teach us that these complex issues can today be investigated by using a physiological and neuroscientific approach. The intricate psychological factors involved can be approached through biochemistry, anatomy, and physiology, thus eliminating the old dichotomy between biology and psychology. This is both a biomedical and a philosophical enterprise that is changing the way we approach and interpret medicine, neurology, and human biology.

In the first case, curing the disease only is not sufficient, and care of the patient is of tantamount importance. In the second case, the philosophical debate about the mind-body interaction can find some important answers.

Although a terminological confusion still persists and the terms placebo effect and response are often used interchangeably, placebo effect could be considered different from placebo response. In the same way as the drug response is the global response to drug administration, so the placebo response is the whole response to placebo administration, including natural history of disease, regression to the mean, and such like.

Conversely, in the same way as the drug effect is the specific pharmacodynamic effect of a drug, so the placebo effect is the specific effect of placebo administration, that is, the real psychobiological phenomenon deriving from the psychosocial context around the patient. What neuroscientists have learned over the past few years is placebos are not inert substances. Instead, they are constituted of different words and therapeutic rituals as well as of different symbolic elements which, in turn, can influence the patient’s brain, thus they are amenable to classic neuroscientific investigation. Therefore, overall, a placebo is the whole ritual of the therapeutic act. Neuroscientists use the placebo effect as a model to understand how the human brain works, and indeed the study of the placebo effect is today a melting pot of concepts and ideas for neuroscience. In fact, there is not a single but many placebo effects, and there is not a single but many mechanisms across different conditions and interventions. The nocebo effect goes in the opposite direction, namely, clinical worsening after negative words that induce negative expectations.

In neurology, the most studied and understood conditions where placebo effects have been investigated in depth are pain and Parkinson’s disease. In pain, the opioid system activation by placebos is the most understood, as shown by the blockade of placebo analgesia by the opioid antagonist naloxone and by in vivo brain imaging of endogenous opioid release. By contrast, the cholecystokinin (CCK)-antagonist, proglumide, enhances placebo analgesia on the basis of the anti-opioid action of CCK, whereas the activation of the CCK type-2 receptors by means of the agonist pentagastrin disrupts placebo analgesia. Therefore, the activation of the CCK type-2 receptors has the same effect as the opioid receptor blockade, which suggests that the balance between CCKergic and opioidergic systems is crucial in placebo responsiveness in pain. Some brain regions in the cerebral cortex and the brainstem are affected by both a placebo and the opioid agonist remifentanil, thus indicating a related mechanism in placebo-induced and opioid-induced analgesia. A role of the CB1 cannabinoid receptors has also been found in some types of placebo analgesia that is not mediated by endogenous opioids. The CCK pro-nociceptive system has also been found to mediate the nocebo hyperalgesic effect. For example, expectation of pain increase leads to nocebo hyperalgesia, and this increase can be blocked by the CCK antagonist proglumide. Interestingly, there is compelling experimental evidence that the whole lipidic pathway, e.g. arachidonic acid, endogenous cannabinoid ligands, prostaglandins and thromboxane, is importantly involved in both placebo and nocebo effects, for example in hypoxia-induced headache.

In Parkinson’s disease, dopamine receptors are activated in both ventral (nucleus accumbens) and dorsal striatum when a placebo is administered. The release of dopamine corresponds to a change of 200% or more in extracellular dopamine concentration, and it is comparable to the response to amphetamine in subjects with an intact dopamine system. Intraoperative single-neuron recording in Parkinson patients during the implantation of electrodes for deep brain stimulation, shows that the firing rate of the neurons in the subthalamic nucleus and substantia nigra pars reticulata decreases after placebo administration, whereas the firing rate of thalamic neurons in the ventral anterior and anterior ventral lateral thalamus increases, along with the disappearance of bursting activity in the subthalamic nucleus. Importantly, from a clinical point of view, these neuronal changes are accompanied by a reduction in muscle rigidity.

It is clear from this brief description that placebos modulate the same biochemical pathways that are modulated by drugs, such as narcotics and non-steroid anti-inflammatory drugs for pain as well as dopaminergic agents for Parkinson’s disease, thus giving rise to the concept that placebos and drugs share common mechanisms of action. Overall, these findings provide compelling evidence for a true pharmacology and toxicology of words and of social interaction, thus leading to a new physiology of the doctor-patient relationship. Much remains to be done to understand where, when and how placebos work, that is, in which medical conditions, in which circumstances, and how they affect the brain across different neurological disorders. This challenge is certainly worth undertaking, as it will provide important pieces of information for clinical practice, clinical trials, and a better understanding of the human brain.•

Fabrizio Benedetti, MD, is professor of neurophysiology at the University of Turin Medical School, Turin, Italy, and professor of medicine, physiology, and neuroscience for the Innovative Clinical Training, Trials and Healthcare Initiative (ICTHI), Zermatt, Switzerland. He has been nominated member of The Academy of Europe and of the European Dana Alliance for the Brain. He is author of the book Placebo Effects (Oxford University Press, 3rd Edition, 2020), which received the Medical Book Award of the British Medical Association in 2009. In 2012, he received the Seymour Solomon Award of the American Headache Society, in 2015 the William S. Kroger Award of Behavioral Medicine from the American Society of Clinical Hypnosis, in 2023 the Lifetime Achievement Award by the Society for Interdisciplinary Placebo Studies.

For additional information:

• Benedetti F, Carlino E, Piedimonte A (2016) Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol, 15: 736-747.
• Benedetti F (2020) Placebo effects. Understanding the other side of medical care. 3rd Edition, Oxford: Oxford University Press.
• Frisaldi E, Zamfira DA, Benedetti F (2021) The subthalamic nucleus and the placebo effect in Parkinson’s disease. In Swaab DF, Kreier F, Lucassen PJ, Salehi A, and Buijs RM (Eds). Handbook of Clinical Neurology: The Human Hypothalamus: Middle and Posterior Region. San Diego: Elsevier BV, pp 433-446.
• Benedetti F, Frisaldi E, Shaibani A (2022) Thirty years of neuroscientific investigation of placebo and nocebo: the interesting, the good, and the bad. Annu Rev Pharmacol Toxicol, 62: 323-340.
• Frisaldi E, Shaibani A, Benedetti F, Pagnini F (2023) Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review. Br Med J Open, 13: e077243.