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Study protocol: exercise training for treating major depressive disorder in multiple sclerosis

Major depressive disorder (MDD) is prevalent, yet sub-optimally treated among persons with multiple sclerosis (MS). We propose that exercise training may be a promising approach for treating depression in pers...

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Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the n...

Beyond gait speed: exploring the added value of Inertial Measurement Unit-based measurements of gait in the estimation of the walking ability in daily life

Gait speed is often used to estimate the walking ability in daily life in people after stroke. While measuring gait with inertial measurement units (IMUs) during clinical assessment yields additional informati...

Cerebral blood flow changes in maintenance hemodialysis patients with restless legs syndrome and their clinical significance:a cross-sectional case-control study

Restless legs syndrome (RLS) stands as a prevalent neurological complication within maintenance hemodialysis (MHD) patients. However, the alterations in cerebral blood flow (CBF) among MHD-RLS patients remain ...

Development of a smartphone screening test for preclinical Alzheimer’s disease and validation across the dementia continuum

Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer’s disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10–20-year ...

Calcitonin gene-related peptide: a possible biomarker in migraine patients with patent foramen ovale

Serum CGRP has been found to increase during migraine attack. However, whether CGRP can identify MA with PFO subtypes in MA remains unknown. This study aimed to investigate the differential expression of calci...

Designing and validating of a questionnaire measuring perceived self-care ability (PSCA) in chronic stroke patients at home

Patients with a stroke often cannot care for themselves after hospital discharge. Assessment of their self-care ability is the first step in planning post-discharge home care. This study aimed to design and va...

Multi-organ involvement caused by Scedosporium apiospermum infection after near drowning: a case report and literature review

Scedosporium apiospermum ( S. apiospermum ) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis.

Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO)

Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We ...

Red blood cell distribution width as a predictor of mortality and poor functional outcome after acute ischemic stroke: a meta-analysis and meta-regression

This study aimed to review evidence on the ability of red cell distribution width (RDW) to predict mortality and poor functional outcomes after acute ischemic stroke (AIS).

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report

Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in ...

Large variations in atrial fibrillation screening practice after ischemic stroke and transient ischemic attack in Sweden: a survey study

Atrial fibrillation (AF) screening after ischemic stroke or transient ischemic attack (TIA) is given high priority in clinical guidelines. However, patient selection, electrocardiogram (ECG) modality and scree...

A novel NODAL variant in a young embolic stroke patient with visceral heterotaxy

Ischemic stroke in young adults can be caused by a variety of etiologies including the monogenic disorders. Visceral heterotaxy is a condition caused by abnormal left–right determinations during embryonic deve...

Adult vasovagal syncope with abdominal pain diagnosed by head-up tilt combined with transcranial doppler: a preliminary study

Syncope is a common condition that increases the risk of injury and reduces the quality of life. Abdominal pain as a precursor to vasovagal syncope (VVS) in adults is rarely reported and is often misdiagnosed.​.

Correction: Photobiomodulation combination therapy as a new insight in neurological disorders: a comprehensive systematic review

The original article was published in BMC Neurology 2024 24 :101

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

The authors sought to examine the impact of the K-variant of butyrylcholinesterase ( BCHE-K ) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers.

Improving emotion perception in cochlear implant users: insights from machine learning analysis of EEG signals

Although cochlear implants can restore auditory inputs to deafferented auditory cortices, the quality of the sound signal transmitted to the brain is severely degraded, limiting functional outcomes in terms of...

Feasibility of a novel eHealth intervention for Parkinson’s disease targeting motor-cognitive function in the home

Parkinson’s disease (PD) drastically affects motor and cognitive function, but evidence shows that motor-cognitive training improves disease symptoms. Motor-cognitive training in the home is scarcely investiga...

Fabry disease in W162C mutation: a case report of two patients and a review of literature

Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or c...

Streptococcus intermedius causing primary bacterial ventriculitis in a patient with severe periodontitis - a case report

Streptococcus intermedius is a member of the S. anginosus group and is part of the normal oral microbiota. It can cause pyogenic infections in various organs, primarily in the head and neck area, including brain ...

Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol

Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in hu...

Exploring vascular contributions to cognitive impairment and dementia (ENIGMA): protocol for a prospective observational study

Post-stroke cognitive impairment (PSCI) is common. However, the underlying pathophysiology remains largely unknown. Understanding the role of microvascular changes and finding markers that can predict PSCI, co...

Guillain–Barre syndrome of acute motor axonal neuropathy (AMAN) type associated with herpes zoster: a case report

Guillain Barre syndrome (GBS) following Varicella zoster is a rare presentation and has only been reported in a few cases around the world. Of the reported cases, the type of GBS is not specified in the majori...

Treatment patterns and persistence on disease modifying therapies for multiple sclerosis and its associated factors

Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing tre...

Migraine treatment: quo vadis ? Real-world data study (2015–2022) in Spain

Migraine is a leading cause of disability, estimated to affect one-in-ten people in Spain. This study aimed to describe the management of migraine in Spain and identify improvement areas.

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease

A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD).

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland

Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnost...

Early ambulation protocol after diagnostic transfemoral cerebral angiography: an evidence-based practice project

No uniform consensus has been achieved regarding the ambulation protocol after transfemoral cerebral angiography (TFA). Until now, in most hospitals patients are prescribed 8-12 h strict immobilization along w...

A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM]

MGMT  (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated wit...

Partial facial paralysis induced by sialolithiasis of the parotid gland: a case report

Facial paralysis due to parotid sialolithiasis-induced parotitis is a unusual clinical phenomenon that has not been reported in prior literature. This scenario can present a diagnostic challenge due to its rar...

Photobiomodulation combination therapy as a new insight in neurological disorders: a comprehensive systematic review

Preclinical and clinical studies have indicated that combining photobiomodulation (PBM) therapy with other therapeutic approaches may influence the treatment process in a variety of disorders. The purpose of t...

The Correction to this article has been published in BMC Neurology 2024 24 :117

Internal stigmatization in patients with chronic migraine and medication overuse headache

Internalized stigma can have profound effects on how individuals with migraines and other primary headache disorders see themselves and their quality of life. We aimed to investigate internalized stigma in pat...

Triple platelet inhibition in intracranial thrombectomy with additional acute cervical stent angioplasty due to tandem lesion: a retrospective single-center analysis

Acute stroke treatment with intracranial thrombectomy and treatment of ipsilateral carotid artery stenosis/occlusion (“tandem lesion”, TL) in one session is considered safe. However, the risk of stent restenos...

Investigating the causal relationship between immune cell and Alzheimer’s disease: a mendelian randomization analysis

Complex interactions between the immune system and the brain may affect neural development, survival, and function, with etiological and therapeutic implications for neurodegenerative diseases. However, previo...

Brain frailty associated with stroke events in anterior circulation large artery occlusion

To investigate the factors associated with brain frailty and the effect of brain frailty in patients with anterior circulation large artery occlusion (AC-LAO).

Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study

The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to devel...

Exploring the role of mitochondrial-associated and peripheral neuropathy genes in the pathogenesis of diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent and serious complication of diabetes mellitus, impacting the nerves in the limbs and leading to symptoms like pain, numbness, and diminished function. While ...

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson’s disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson’s disease

Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson’s disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose o...

Optimized MLPA workflow for spinal muscular atrophy diagnosis: identification of a novel variant, NC_000005.10:g.(70919941_70927324)del in isolated exon 1 of SMN1 gene through long-range PCR

Spinal muscular atrophy (SMA) is a rare autosomal recessive hereditary neuromuscular disease caused by survival motor neuron 1 ( SMN1 ) gene deletion or mutation. Homozygous deletions of exon 7 in SMN1 result in 95...

Detection limitations of prion seeding activities in blood samples from patients with sporadic prion disease

Human prion diseases (HPDs) are fatal neurodegenerative disorders characterized by abnormal prion proteins (PrPSc). However, the detection of prion seeding activity in patients with high sensitivity remains ch...

A systematic review and meta-analysis of clinical efficacy of early and late rehabilitation interventions for ischemic stroke

At present, stroke has become the first cause of death and disability among Chinese adults. With the coming of the aging population in China, the disease burden brought by stroke will be increasingly aggravate...

High thrombin-activatable fibrinolysis inhibitor expression in thrombi from stroke patients in elevated estrogen states

The risk of acute ischemic stroke (AIS) associated with high estrogen states, including pregnant patients and those using oral contraceptives, has been well documented. We described the histological compositio...

Neuroanatomical and neurocognitive correlates of delusion in Alzheimer’s disease and mild cognitive impairment

Neuropsychiatric symptoms and delusions are highly prevalent among people with dementia. However, multiple roots of neurobiological bases and shared neural basis of delusion and cognitive function remain to be...

Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients

Hypertriglyceridemia (HT) may increase the risk of stroke. Limited studies have shown that stroke severity and infarction size are smaller in patients with HT. We explored the relationship between triglyceride...

Expanded clinical phenotype and untargeted metabolomics analysis in RARS2 -related mitochondrial disorder: a case report

RARS2 -related mitochondrial disorder is an autosomal recessive mitochondrial encephalopathy caused by biallelic pathogenic variants in the gene encoding the mitochondrial arginyl-transfer RNA synthetase 2 ( RARS2 ,...

The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events

The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary ob...

Relationship between glycated hemoglobin levels and three-month outcomes in acute ischemic stroke patients with or without diabetes: a prospective Korean cohort study

In patients experiencing acute ischemic stroke, there is ongoing debate surrounding the connection between chronic hyperglycemic status and their initial clinical outcomes. Our objective was to examine the con...

Questionnaire-based study of COVID-19 vaccination induced headache: evidence of clusters of adverse events

The adverse events (AEs) after a Coronavirus disease 2019 (Covid-19) Pfizer-Biotech mRNA vaccination present a medical and epidemiological issue of increasing interest. Headache is the most frequent neurologic...

Hand knob sign in osmotic demyelinating syndrome

Osmotic demyelinating syndrome, commonly recognized as a consequence of the rapid correction of hyponatremia, has been known to cause motor, neuropsychiatric, or extrapyramidal symptoms. We reported a patient ...

Case identification of non-traumatic brain injury in youth using linked population data

Population-level administrative data provides a cost-effective means of monitoring health outcomes and service needs of clinical populations. This study aimed to present a method for case identification of non...

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A ‘Havana Syndrome’ Investigation in Congress Rests on Politics, Not Science

Lawmakers should look in the mirror if they want answers to who hyped dubious reports of Havana syndrome. Instead they are investigating the spy agencies telling them the truth about the mystery

Robert Bartholomew

Growth Hormone Injections May Have ‘Seeded’ Alzheimer’s in Some People, Study Suggests

Injections of no-longer-used growth hormone derived from cadavers may have “seeded” Alzheimer’s in some people, small study suggests

Carissa Wong, Nature magazine

Elon Musk’s Neuralink Has Implanted Its First Chip in a Human Brain. What’s Next?

The wealthiest person on Earth has taken the next step toward a commercial brain interface

Ben Guarino

Zapping the Vagus Nerve Could Relieve Some Long COVID Symptoms

Ongoing research shows electrical vagus nerve stimulators could relieve some long COVID symptoms. But are the expensive devices worth the price?

A Rare Visual Disorder Twists Faces Out of Shape

New studies unlock the mysteries of prosopometamorphopsia, a disorder that distorts faces. One woman’s condition improves when she wears orange-tinted glasses

Jaimie Seaton

Could Blood Transfusions and Tissue Transplants Spread Certain Dementias?

Scattered evidence suggests that aberrant proteins act as “seeds” to transmit neurodegenerative disease, but the jury is still out

Esther Landhuis

Transgender People’s Neurological Needs Are Being Overlooked

Migraine, stroke and epilepsy disproportionately affect members of the transgender community—but neurologists are often unprepared to respond

Z Paige L'Erario

How Does Your Brain Remember and Retrieve Words?

Here's a look at how the brain uses its mental dictionary to remember and retrieve language

Nichol Castro, The Conversation

Man with Parkinson’s Walks Smoothly thanks to an Experimental Spinal Implant

Electrical stimulation to the lower spine has improved the mobility of a man with Parkinson’s disease for the past two years, but researchers say larger clinical trials are needed to assess the device  

Emily Waltz, Nature magazine

Scientists Tickle Rats and Discover Brain’s ‘Play Spot’

By inhibiting part of rats’ brain stem, scientists may have found the play center of the brain

Timmy Broderick

How Dangerous Are Soccer Concussions? They May Cause Lasting Damage

As the 2023 Women’s World Cup kicks off, repeated concussions and head injuries in the sport raise discussion about the lifelong consequences on the brain

Lauren J. Young

The First Person to Be Diagnosed with Autism Has Died at 89

A 1943 paper highlighted “Donald T.” as “Case 1” of 11 children with “autistic disturbances of affective contact”

Shaena Montanari, Spectrum

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings

• Claudia Pestchanker
• Brenda Bertado Cortez
• Edgar Carnero Contentti

Frontal hypometabolism in the diagnosis of progressive supranuclear palsy clinical variants

• Jack A. Black
• Nha Trang Thu Pham
• Jennifer L. Whitwell

Effect of siponimod on lymphocyte subsets in active secondary progressive multiple sclerosis and clinical implications

• Antonio Luca Spiezia
• Giulia Scalia
• Antonio Carotenuto

Respiratory comorbidities and treatments in Duchenne muscular dystrophy: impact on life expectancy and causes of death

• Lisa Wahlgren
• Anna-Karin Kroksmark
• Kalliopi Sofou

Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis

• Dalit Barel
• Daphna Marom
• Hagit Baris Feldman

Clinical trial evidence of quality-of-life effects of disease-modifying therapies for multiple sclerosis: a systematic analysis

• Julian Hirt
• Kinga Dembowska
• Perrine Janiaud

TMS of the left primary motor cortex improves tremor intensity and postural control in primary orthostatic tremor

• Florian Schoeberl
• James Dowsett
• Andreas Zwergal

Which parameters influence cognitive, psychiatric and long-term seizure outcome in mesial temporal lobe epilepsy after selective amygdalohippocampectomy?

• Harald Stefanits
• Ekaterina Pataraia

Applying the 2022 optic neuritis criteria to noninflammatory optic neuropathies with optic nerve T2-hyperintensity: an observational study

• Fernando Labella Álvarez
• Valérie Biousse
• Nancy J. Newman

Early use of high-efficacy therapies in multiple sclerosis in the United States: benefits, barriers, and strategies for encouraging adoption

• Barry A. Singer
• Horacio Chiong-Rivero

Amyloid antibody therapy for early-stage Alzheimer’s disease: a critical review of three recent trials

• A. E. Guiloff

Improving the sensitivity of myelin oligodendrocyte glycoprotein-antibody testing: exclusive or predominant MOG-IgG3 seropositivity—a potential diagnostic pitfall in patients with MOG-EM/MOGAD

• M. Ringelstein
• B. Wildemann

Healthy blood, healthy brain: a window into understanding and treating neurodegenerative diseases

• Thyago R. Cardim-Pires
• Aurélie de Rus Jacquet
• Francesca Cicchetti

Effects of dopaminergic therapy on sleep quality in fluctuating Parkinson’s disease patients

• Claudia Ledda
• Alberto Romagnolo
• Maurizio Zibetti

The role of language-related functional brain regions and white matter tracts in network plasticity of post-stroke aphasia

• Yuanyuan Jing

Accuracy of routinely collected hospital administrative discharge data and death certificate ICD-10 diagnostic coding in progressive supranuclear palsy and corticobasal syndrome: a systematic review and validation study

• Diane M. A. Swallow
• Carl E. Counsell

A survey-based approach on restless legs syndrome: practices and perspectives among Italian neurologists

• Elena Antelmi
• Gloria Pompea Mingolla
• Michele Tinazzi

Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights

• Andy Cheuk-Him Ng
• Mohamed Chahine
• Juan P. Appendino

Exosomes for neurodegenerative diseases: diagnosis and targeted therapy

Bispecific BCMA/CD19 targeted CAR-T cell therapy forces sustained disappearance of symptoms and anti-acetylcholine receptor antibodies in refractory myasthenia gravis: a case report

An anti-PF4 antibody-related disorder with cerebral venous sinus thrombosis and thrombocytopenia initially presenting as intracranial hemorrhage

• Matthias Wittstock
• Daniel Cantré
• Thomas Thiele

Endovascular thrombectomy with versus without intravenous thrombolysis in patients with acute basilar artery occlusion: a systematic review and meta-analysis

• Liaoyuan Wang

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme

• Neil Watson
• Suvankar Pal

Clinical and neuroanatomical characterization of the semantic behavioral variant of frontotemporal dementia in a multicenter Italian cohort

• Alma Ghirelli
• Edoardo Gioele Spinelli
• Federica Agosta

The motor band sign differentiates hereditary spastic paraplegia from the others upper motor neuron syndromes

• Graziella Donatelli
• Francesca Bianchi
• Mirco Cosottini

Accelerated long-term forgetting reveals everyday memory deficits in early-stage multiple sclerosis

The grasp reflex in patients with idiopathic normal pressure hydrocephalus

• Shigenori Kanno
• Kyoko Suzuki

Functional connectivity changes in neurodegenerative biomarker-positive athletes with repeated concussions

• Indira Garcia-Cordero
• Anna Vasilevskaya
• Maria C. Tartaglia

Progression to corticobasal syndrome: a longitudinal study of patients with nonfluent primary progressive aphasia and primary progressive apraxia of speech

• Danna P. Garcia-Guaqueta
• Keith A. Josephs

Naming fMRI-guided white matter language tract volumes influence naming decline after temporal lobe resection

• Karin Trimmel
• Sjoerd B. Vos
• John S. Duncan

NFL and GFAP in (pre)symptomatic RVCL-S carriers: a monogenic cerebral small vessel disease

• Annelise E. Wilms
• G. M. Terwindt

Peripheral immune profile in drug-naïve dementia with Lewy bodies

• Tadashi Umehara
• Masahiro Mimori
• Yasuyuki Iguchi

Correction to: Implementation of a 7T Epilepsy Task Force consensus imaging protocol for routine presurgical epilepsy work-up: effect on diagnostic yield and lesion delineation

• Gilbert Hangel
• Gregor Kasprian
• Karl Roessler

Correction to: Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management

• Tania Kümpfel
• Katrin Giglhuber
• The Neuromyelitis Optica Study Group (NEMOS)

Risk of hepatitis B virus reactivation in people with multiple sclerosis treated with ocrelizumab: an observational study from Turkey

• Muammer Çelik
• Vildan Avkan-Oğuz

Endothelial receptor proteins in acute venous thrombosis and delayed thrombus resolution in cerebral sinus vein thrombosis

• Lukas Kellermair
• Christoph Höfer
• Milan R. Vosko

Keeping prior anticoagulation treatment in the acute phase of ischaemic stroke: the REKOALA study

• Ricardo Rigual
• Jorge Rodríguez-Pardo
• Blanca Fuentes

Ticagrelor versus clopidogrel in dual antiplatelet therapy after minor stroke or transient ischemic attack: an updated network meta-analysis

• Gabriel Marinheiro
• Beatriz Araújo
• João Paulo Mota Telles

Inter-laboratory comparison of routine autoantibody detection methods for autoimmune neuropathies and myasthenia gravis

• Laura Martínez-Martínez
• Anna Calvet Lacruz
• The 2022 GEAI-S. E. I. Workshop participants

A multimodal clinical diagnostic approach using MRI and 18 F-FDG-PET for antemortem diagnosis of TDP-43 in cases with low–intermediate Alzheimer’s disease neuropathologic changes and primary age-related tauopathy

• Anna Lavrova

Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations

• Jun Ikezawa
• Fusako Yokochi
• Kazushi Takahashi

Takotsubo cardiomyopathy in Guillain–Barré syndrome

• Atsushi Terayama
• Motoi Kuwahara
• Yoshitaka Nagai

Prevalence and epidemiology of stroke in patients with multiple sclerosis: a systematic review and meta-analysis

• Maria-Ioanna Stefanou
• Vasileios Giannopapas
• Georgios Tsivgoulis

Pregnancy effect on disease activity in women with multiple sclerosis treated with cladribine

• E. Signoriello
• S. Bonavita

Acute recanalization therapy for ischemic stroke during pregnancy and puerperium

• Anna Richardt
• Karoliina Aarnio

ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis

• Elisabetta Maida
• Marcello Moccia
• Digital Technologies, Web, Social Media Study Group of the Italian Society of Neurology (SIN)

Correction to: Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study

• Piero Barbanti
• Cinzia Aurilia
• for the Italian Migraine Registry study group

Subjective BPPV revisited: identification of positional nystagmus with a new maneuver

• Hyun-Jae Kim
• Young-Eun Gil

Can treatment adverse events be optimized by switching between different sphingosine 1-phosphate receptor modulators in multiple sclerosis? A case series

• Simone Guerrieri
• Martina Rubin
• Lucia Moiola

Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series

• Shanice Beerepoot
• Jaap Jan Boelens
• Nicole I. Wolf

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SYSTEMATIC REVIEW article

Diagnosis and therapies for patients with cerebral palsy over the past 30 years: a bibliometric analysis.

• 1 Department of Outpatient, Hangzhou Children's Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
• 2 Department of Radiology, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang, China
• 3 Department of Neurosurgery, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang, China
• 4 Department of Neurosurgery, People's Hospital of Haimen District, Nantong, Jiangsu, China
• 5 Department of Neurosurgery, Hangzhou Children's Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China

Background: Currently, the incidence of cerebral palsy is high in newborns. However, the current methods for diagnosing and treating patients with cerebral palsy are complex and poorly targeted. Moreover, these studies lack the support of bibliometric analysis results.

Objective: Our study focused on a bibliometric analysis of published papers on the diagnosis and treatment of patients with cerebral palsy. This study identified the primary authors, institutions, and countries involved in analyzing the status and trends of research on the diagnosis and treatment of patients with cerebral palsy. Additionally, the study also involved screening pathways related to cerebral palsy.

Methods: The PubMed database was searched for publications on the diagnosis and treatment of patients with cerebral palsy between 1990 and 2023. R v4.2.2 and VOSviewer v1.6.18 software tools were utilized to perform bibliometric analysis and visualization.

Results: There were 1,965 publications on cerebral palsy diagnosis and 5,418 articles on the qualified treatment strategies, and the annual number of publications also increased. The United States dominated in this field of research. Gregory Y.H. Lip and Patrizio Lancellotti published the most number of papers. The Cleveland Clinic published the most number of papers in the field. According to the analysis of the co-occurrence of keywords, we found that the main research directions were age, sex, disease diagnosis, and treatment. Newly emerging research has focused mainly on heart failure, which is related to valvular heart disease.

Conclusion: The findings presented in this study offer valuable insights into ongoing research and potential future directions pertaining to cerebral palsy. These insights can assist researchers in identifying suitable collaborators and enhancing their investigations aimed at identifying the underlying molecular mechanisms associated with cerebral palsy, encompassing its etiology, preventive measures, and therapeutic interventions.

Introduction

Cerebral palsy (CP) is not a clear, separate disease classification but rather an umbrella term that includes miscellaneous signs and symptoms that change with age. Cerebral palsy is diagnosed primarily through motor function and posture disorders and typically develops in early childhood and persists throughout life. These disorders are not progressive but change with age ( 1 , 2 ). Motor dysfunction is a fundamental manifestation of cerebral palsy and frequently co-occurs with additional impairments encompassing sensory, perceptual, cognitive, communicative, and behavioral disorders; epilepsy; and secondary musculoskeletal complications ( 3 ). Cerebral palsy occurs in 2–3 infants out of 1,000 live births ( 4 ). There are multiple causes of brain damage that affect movement, posture, and balance. Motor disorders associated with cerebral palsy can be classified as spasms, motor disorders, ataxia, or mixed/other disorders ( 5 ). The symptoms of cerebral palsy include movement disorders, hip dislocations, balance difficulties, and hand dysfunction. In cases of cerebral palsy without a clear cause, magnetic resonance imaging may help diagnose brain damage when there is no clinical diagnosis. Once cerebral palsy is diagnosed, instruments such as the hair motor function classification system can be used to assess its severity and treatment response. The treatment of motor disorders associated with cerebral palsy includes intramuscular botulinum toxin A, medications, selective dorsal rhizotomy, and physiotherapy could be used to treat a wide range of muscle disorders. Patients with cerebral palsy often experience problems that are not related to movement and that need to be addressed in adulthood; these problems include cognitive impairment, seizures, pressure sores, osteoporosis, behavioral or emotional problems, and speech and hearing impairment ( 6 ).

The visual analysis software used for literature analysis included R v4.2.2 and VOSviewer, which play important roles in analyzing the current state of scientific research, detecting disciplinary frontiers, and selecting research directions. Bibliometrics can provide us with information on the most influential factors (including countries, institutions, and authors) in the field we want to study through relevant publications. In a manner, this approach could provide researchers with potentially favorable directions for their research. Currently, there is no research summarizing the treatment and diagnosis of cerebral palsy.

The identification of the relationships between the molecular and pathological levels of pathways and between the diagnosis and therapies used in patients with cerebral palsy can provide a basis for understanding the pathogenesis of cerebral palsy to some extent. However, there have been few bibliometric studies on the diagnosis/therapies of patients with cerebral palsy. Based on our bibliometric analysis, we generated data on cerebral palsy to provide insights for researchers who seek to discover new topics and directions.

Materials and methods

Data selection.

We screened the PubMed database for the period from 1 January 1990 to 20 January 2023 to identify publications related to the diagnosis and treatment of patients with cerebral palsy. We considered only English-language publications. The title and abstract were reviewed and screened by two independent reviewers (Lili Jiang and Song Zhang), and disagreements were resolved.

Data analysis and visualization

Key information (e.g., title, author, country/region, institution, keywords, and the year of publication) was derived from our included articles that met the inclusion criteria. The above variables were processed and visualized using Python v3.10.8, R v4.2.2, and VOSviewer v1.6.18.

VOSviewer was applied to perform the network analysis of the authors and frequent keywords. The minimum number of occurrences of a keyword was seven, which was the parameter of VOSviewer. A country collaboration map and various chart drawings based on the bibliometrix R package were constructed.

Pathway enrichment analysis

We downloaded canonical pathway gene sets based on the Reactome pathway database from the GSEA database ( 7 ). The pathway enrichment analysis of the GSE183021 ( 8 ) dataset was performed using the GSVA R package ( 9 ). The differential gene expression analysis of pathway scores was performed based on the limma R package ( 10 ).

General information

A total of 7,383 publications were identified from PubMed. Of these, 1,965 publications were based on diagnosis, and 5,418 publications were based own treatment. We created two boxplots ( Figure 1 ) to represent the number and ratio of annual publications over the last 33 years, which indicated the development trend of related research in this field. This field continues to attract the attention and interest of researchers, as evidenced by the growing number of publications. Research on the promotion of different diseases has shown differences in the associations between diagnosis and treatment.

Figure 1 . The number of annual publications relating to research on the diagnosis and treatment of cerebral palsy from 1990 to 2023. (A) The number of studies related to cerebral palsy diagnosis from 1990 to 2023. (B) The number of studies related to cerebral palsy treatment from 1990 to 2023. (C) A comparison of the annual journal publications related to cerebral palsy diagnosis and treatment.

Compared to diagnostic research, the treatment of cerebral palsy received more attention from 1990 to 2023. In summary, our results showed that the diagnosis and treatment of patients with cerebral palsy have gained widespread attention.

Distribution of authors

The top 10 authors were involved in more than 10 papers on the diagnosis and treatment of patients with cerebral palsy, most of which were published in Europe and Australia ( Tables 1 , 2 ). The bar chart shows that most of the studies originated from the United States and were mainly single-country studies ( Figure 2 ). The author collaboration network visualization ( Figure 3 ) was performed on VOSviewer.

Table 1 . The top 10 authors published articles on the diagnosis of cerebral palsy.

Table 2 . The top 10 authors published articles on the therapy for cerebral palsy.

Figure 2 . Boxplot of countries engaged in research on the diagnosis (A) and treatment (B) of cerebral palsy.

Figure 3 . The network of authors who contributed to the research on the diagnosis (A) and treatment (B) of cerebral palsy. In the network, author contributions are reflected by node size. The connection strength is reflected by the thickness of the line.

Distribution of countries/territories and institutions

The top 10 institutions had over 937 ( Figure 4A ) and 1,105 ( Figure 4B ) articles on the diagnosis and treatment of patients with cerebral palsy, respectively. According to the country collaboration map, we found that the research was mostly distributed in Europe and was closely related to many regions ( Figure 5 ).

Figure 4 . The treemap of institutions engaged in research on the diagnosis (A) and treatment (B) of cerebral palsy.

Figure 5 . A country collaboration map of the research on the diagnosis (A) and treatment (B) of cerebral palsy.

Analysis of keywords and research direction analysis

The results of keyword analysis not only help us understand the topic of the article but also help us understand the hot spots in a research area. The top 20 keywords with the highest frequency are listed in Tables 3 , 4 . As shown in Figure 6 , we used VOSviewer to display the network of keywords.

Table 3 . The top 20 keywords for the diagnosis of cerebral palsy.

Table 4 . The top 20 keywords related to therapy for cerebral palsy.

Figure 6 . The network visualization of keywords related to the diagnosis (A) and treatment (B) of cerebral palsy. A keyword's weight is represented by the size of its circle. The distance between two circles indicates the relatedness between the two circles. Shorter distances are associated with stronger relatedness. The different colors of the circles represent the cluster classes.

The heat map did not reveal relatively important results in the field of diagnosis, but, during treatment, we found that the individual may be more important in the clinical treatment of cerebral palsy ( Figure 7 ).

Figure 7 . Thematic map of the research on the diagnosis (A) and treatment (B) of cerebral palsy. In the thematic map, the horizontal axis represents the centrality and the vertical axis represents the density. Motor themes: these themes are important and well-developed. Niche themes: these themes are very specialized/niche themes that are well-developed but are not important for the current field. Emerging or declining themes: these themes are not well-developed, may just emerge, or may soon disappear. Basic themes: these themes are very important to the field and have not achieved good development.

We downloaded the Reactome pathway dataset, subjected it to enrichment analysis to obtain the fractional matrix of the pathways, and conducted differential analysis to obtain the differential heatmap of cerebral palsy-related pathways ( Figure 8 ).

Figure 8 . Pathway enrichment analysis of the expression matrix in cerebral palsy patients.

We identified 3,089 pathways enriched in cerebral palsy, including 56 upregulated pathways (logFC > 0, P < 0.01) and 10 downregulated pathways (logFC < 0, P < 0.01).

In relation to publishing patterns, our analysis reveals a steady upward trajectory in the number of publications pertaining to this domain since 1990. This trend suggests that both fields will continue to garner significant interest from researchers in the coming years. Moreover, the authors' collaborative network analysis offers a valuable tool for researchers to foster collaborative associations, as it enables the identification of influential research groups and potential partners.

Most of the authors listed in Tables 1 , 2 are located in Europe/Australia, and the relationships between European scholars are much closer than those between scholars in other regions. As shown in Figure 2 , many authors have made contributions to this field, but their cooperation needs to be strengthened. Figure 4 shows that most well-published institutions are located in the United States. For the current research, the active cooperation and exchange of ideas between researchers/research institutions in various countries will be beneficial to the development of this field.

Study hotspots

We have not mined important research directions from the diagnosis section, but we have found that the basic themes for the diagnosis section are similar to the motor themes for the treatment section. The basic criteria for diagnoses included studies on humans (1,653), female (1,047), male (944), child, preschool (623), infant (515), infant or newborn (445) factors; retrospective studies (307); information on risk factor (200); pregnancy (176); and follow-up studies (133).

The motor themes for the treatment included studies on humans (4,474), child (2,790), female (2,641), male (2,483), child, preschools (1,614), adolescent (1,537), treatment outcome (1,160), adult (687), retrospective studies (591), and cerebral palsy/complications (514). However, to some extent, these results do not explain some of the details, thus we combined them with keyword analysis.

Research has shown that cerebral palsy or “high risk of cerebral palsy” can be accurately predicted before the corrected age of 6 months, and detecting cerebral palsy before the corrected age, including magnetic resonance imaging (MRI), has the best predictive effectiveness, with a sensitivity of 86–89% ( 11 ).

Magnetic resonance imaging (MRI) can help assess the duration of brain damage during the development of cerebral palsy (CP) ( 12 ). MRI can also be used to assess white matter damage in premature infants and is therefore more common in the field of cerebral palsy diagnosis ( 13 ).

Therefore, the development of MRI technology and the discovery of cerebral palsy monitoring indicators have become increasingly important. In the biological and molecular research fields, finding more accurate monitoring indicators is particularly important ( 14 , 15 ).

The keywords used for the treatment of cerebral palsy include muscle spasticity and physical therapy modifications. The treatment of cerebral palsy (CP) includes physical therapy and complementary therapies to various standard clinical treatments ( 16 ).

The prenatal diagnosis of cerebral palsy relies on routine ultrasound examinations, which mainly detect congenital malformations and other diseases, but there is currently no specific method for treating cerebral palsy ( 17 ). Research ( 18 ) has summarized the risk factors for cerebral palsy, such as chorioamnionitis, maternal infection, neurotropic virus infection, any virus from Herpes Group B for hemiplegia, and infection of the mother with cytomegalovirus during the first trimester.

Therefore, in the absence of significant progress in imaging, biochemistry, and other related research fields, the discovery of key genes and therapeutic targets in genetics for cerebral palsy will promote the development of methods for diagnosing and treating cerebral palsy.

Future frontiers

Due to the extensive screening of diagnosis and treatment, we observed a relatively significant clinical situation. Imaging is used for the diagnosis of cerebral palsy, while physical therapy and some auxiliary treatments are used for the clinical treatment of cerebral palsy. At the molecular level, research on cerebral palsy

is relatively scarce. Currently, relatively few studies on neurons, muscle contractures, and genes exist; these studies have not been fully examined through bibliometric analysis of the literature. Research on the underlying mechanism of cerebral palsy is not particularly abundant, but, in combination with other research studies on diseases and a small amount of basic research, we speculate that research on the molecular mechanisms will provide evidence for the diagnosis and treatment of cerebral palsy to some extent.

The “Activation of the Ap 1 Family of Transcription Factors” was the most significantly differentially expressed pathway. A previous study showed that gene mutations in AP-1-related transcription factor complexes can affect brain development ( 19 ).

The “Akt Phosphorylates Targets in the Cytosol” represents the presence of phosphorylated Akt in the cytoplasm. Studies have shown that the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway enhances neurogenesis ( 20 ). Our study showed that Akt phosphorylation was downregulated in patients with NAFLD compared to healthy individuals ( Figure 8 ).

This study examined a comprehensive collection of 7,383 publications spanning from 1990 to 2023 that specifically address valvular diagnosis and therapies in patients with cerebral palsy. The objective of this research is to identify the countries, institutions, and authors that have had significant impacts on this field. Furthermore, our investigation focuses on specific topics to discern prevailing research patterns. Additionally, we employed GSVA R package to explore common pathways associated with cerebral palsy. Although cerebral palsy is a congenital disease, clinical detection has been less common but should be the focus of future research. Although the molecular mechanisms involved have not been the focus of current research, these mechanisms will provide a basis for the drug treatment to some extent.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Author contributions

LJ: Project administration, Writing – original draft. WY: Writing – original draft. HC: Data curation, Writing – review & editing. HS: Data curation, Writing – review & editing. SZ: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by Hangzhou, Zhejiang Province, Biomedical and Health Industry Development Support Science and Technology Special Project (2023WJC326).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2024.1354311/full#supplementary-material

Figure S1. A flowchart of literature identification and selection.

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Keywords: cerebral palsy, bibliometric analysis, visual analysis, diagnosis, therapy

Citation: Jiang L, Yang W, Chen H, Song H and Zhang S (2024) Diagnosis and therapies for patients with cerebral palsy over the past 30 years: a bibliometric analysis. Front. Neurol. 15:1354311. doi: 10.3389/fneur.2024.1354311

Received: 12 December 2023; Accepted: 20 March 2024; Published: 17 April 2024.

Reviewed by:

Copyright © 2024 Jiang, Yang, Chen, Song and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Song Zhang, zhsg1049@163.com

† These authors have contributed equally to this work and share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Precision Medicine for Parkinson’s Disease Is Focus of New Yale Center

Clemens Scherzer, MD , is on a mission to revolutionize the treatment of Parkinson’s disease through the use of genomics and artificial intelligence (AI) to create tailored therapeutics. In January, Scherzer joined Yale School of Medicine (YSM) and stepped into his new role as director of the Stephen & Denise Adams Center for Parkinson’s Disease Research. The center’s unique approach to developing the future of precision medicine for Parkinson’s disease is the first of its kind, he says.

“Right now, we wait for Parkinson’s disease to progress and cause debilitating symptoms that drive the patient to the clinic, where we scramble to catch up with treating them,” says Scherzer. “Through our new center, we want to learn to catch the disease early, be able to predict what the future will hold for each patient, and then intervene to prevent debilitating progression from ever occurring.”

Researchers will identify targets for new Parkinson’s disease medications

Scherzer envisions a future in which a person with Parkinson’s disease can walk into a clinic and provide a few drops of blood that a computer program can analyze to identify the patient’s genome and biomolecules. Clinicians would be able to use this information in addition to the patient’s electronic health data to determine the exact disease driver and to recommend precision therapeutics based on tailored biomarkers.

“Our work is similar to how a search engine targets advertisements to a user based on massive search histories,” he explains. “The goal is to precisely match the right drug to the right person at the right time, based on a search of the entire disease biology.”

To make this vision a reality, Scherzer and his team are building a multi-modal human atlas of Parkinson’s disease by cataloging molecular and clinical data from thousands of patients. Scherzer began this work while at Harvard Medical School, where he was professor of neurology, director of the American Parkinson’s Disease Association (APDA) Center for Advanced Parkinson Research, and director of the Precision Neurology Program at Brigham and Women’s Hospital. He will be advancing these efforts at YSM.

So far, Scherzer’s team has already sequenced the RNA programs of one million human brain cells spanning the entirety of disease progression—from healthy brains, to those in the earliest stages of Parkinson’s, to those in the most advanced manifestations of the disease.

Other ongoing work that also will be expanding at the Yale center includes the Yale Harvard Biomarkers Study, which involves mapping the genetic variants that control the course of Parkinson’s and using multi-omics technology to catalog molecules in patients’ biofluids. The biobank already has hundreds of thousands patient samples of DNA, RNA, plasma, and more—stored at the Yale Adams Center and with collaborators at Mass General Brigham—that he and his program have extensively characterized over several years as patients’ disease advanced. “This is a treasure trove for discovery of genes, therapeutics, and biomarkers,” says Scherzer.

The goal is to precisely match the right drug to the right person at the right time, based on a search of the entire disease biology. Clemens Scherzer, MD

For example, approximately 10% of patients with sporadic Parkinson’s disease [in which the patient has no clear familial history] have a mutation in a gene known as GBA . Researchers have discovered four different types of genetic variants of this gene that regulate the speed of progression of the disease. Those with the most severe mutation suffer a very rapid progression of their condition. After identifying this disease driver, a research team Scherzer led at Harvard collaborated with a pharmaceutical company to target this gene with precision medicine. The collaboration contributed to the first Phase 2 clinical trial focused on a genetic form of Parkinson’s and provided a tool kit for precision trials targeting GBA .

Scherzer hopes to use the power of genomics and AI to turn data into medicine. The center is using computational neuroscience and machine learning to accelerate research. “With powerful sequencing and computational technologies, we can look at 30,000 genes in a million brain cells in parallel and let biology tell us what is truly important to work on.”

Paving the way to precision medicine for Parkinson’s disease

Now, Scherzer’s ambitions include identifying other disease drivers and learning how to target them. “We’re on a quest to decode the RNA software of brain cells and figure out how to develop tailored drugs that correct any glitches,” he says. “Then, our goal is to launch early-stage clinical trials based on our newly identified drug targets.”

To fast-track drug development, the researchers are utilizing electronic patient data from entire populations and from their Yale Harvard Biomarkers Study to find old drugs that could be repurposed for Parkinson’s patients. In collaboration with the University of Bergen in Norway, Clemens’ team is using computer models to compare health outcomes recorded over a decade in thousands of individuals with Parkinson’s disease on a medication compared to millions of individuals with Parkinson’s not on the medication. “We are searching for old drugs that can be taught new tricks to help patients with Parkinson’s disease,” says Scherzer.

This search is identifying drugs for possible repurposing, including medications commonly used for asthma known as beta2 agonists. In the lab, the researchers observed that in neurons grown in a dish, the asthma drugs lowered the activity of the alpha-synuclein gene and improved the cells’ health. “This was intriguing because the brains of Parkinson’s patients are full of Lewy bodies, which are piles of alpha-synuclein,” says Scherzer. “Dialing down alpha-synuclein levels would be ideal to correct this disease driver.”

Several beta2 agonists are currently in clinical trials. Scherzer and colleagues hope that their repurposing platform will spur even more clinical trials.

A central goal of the Yale center is to develop new and more effective Parkinson’s disease medications that slow or block disease progression and prevent disabling symptoms from ever occurring. “We already have dopamine replacement medicines that treat patients very well for several years, but then debilitating complications develop,” says Scherzer. “If we can identify drugs that extend this therapeutic window for 10 years or more, many patients will never suffer these complications.”

His longer-term vision is to one day build a precision neurology clinic where those living with Parkinson’s disease receive personalized treatments. “We are going to change patients’ lives,” says Scherzer.

Featured in this article

• Clemens Scherzer, MD Director of the Stephen & Denise Adams Center for Parkinson’s Disease Research

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eAppendix. ROC Curve Analysis

eFigure. ROC Curves of PCL-C Scores and NODDI/DTI Metrics Classifying mTBI From Control

eTable 1. Index of ROIs From the JHU-ICBM-DTI-81 WM Labels Atlas

eTable 2. Severity Ratings of GAD-7 and PHQ-9

eTable 3. Results of Sensitivity Analysis of Regression Models (TBI Only, n = 65)

eTable 4. Diagnostic Sensitivity and Specificity of PCL-C Scores and Diffusion Parameters for Classifying mTBI From Control

eReferences.

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White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury

• 1 Program in Neuroscience, Uniformed Services University of Health Sciences, Bethesda, Maryland
• 2 School of Medicine, Uniformed Services University of Health Sciences, Bethesda, Maryland
• 3 National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Bethesda, Maryland
• 4 Department of Preventive Medicine and Biostatistics, Uniformed Services University of Health Sciences, Bethesda, Maryland
• 5 Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
• 6 Directorate of Behavioral Health, Walter Reed National Military Medical Center, Bethesda, Maryland
• 7 Department of Neurology, Walter Reed National Military Medical Center, Bethesda, Maryland

Question   Can the use of diffusion tensor imaging and neurite orientation dispersion and density imaging effectively detect white matter microstructural alterations in US military service members with a history of mild traumatic brain injury occurring more than 2 years ago, and can the results be used in monitoring neurobehavioral symptoms?

Findings   In this case-control study of 98 military service members, both imaging tools detected widespread differences in white matter, with more sensitive results occurring with the use of neurite orientation dispersion and density imaging metrics through a region-of-interest approach. Notably, these white matter alterations were found to be associated with neurobehavioral symptoms.

Meaning   These findings support the usefulness of advanced neuroimaging techniques in assessing microstructural changes related to military-related mild traumatic brain injury, and suggest that aberrant white matter properties can be used in monitoring progression or recovery during the chronic postinjury phase.

Importance   Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis.

Objective   To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI).

Design, Setting, and Participants   This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age.

Exposures   Remote history of mTBI.

Main Outcomes and Measures   White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed.

Results   A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P  < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (β = −0.029, Cohen d  = 0.66; P  < .001), ODI of the left posterior thalamic radiation (β = −0.006, Cohen d  = 0.55; P  < .001), and ODI of the left uncinate fasciculus (β = 0.013, Cohen d  = 0.61; P  < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (β = 5.4 × 10 −3 ; P  = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (β = 4.3 × 10 −4 ; P  = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (β = 1.2 × 10 −3 ; P  = .02).

Conclusions and Relevance   In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

Traumatic brain injury (TBI) is a significant health concern, particularly among military populations. According to the Defense and Veterans Brain Injury Center (DVBIC), more than 450 000 TBIs among US service members worldwide have been reported between 2000 and 2022, with over 80% of those TBIs being classified as mild (mTBI). 1 Mounting evidence has demonstrated the neuropsychiatric consequences of mTBI, including chronic postconcussion symptoms and serious long-term effects on cognition, memory, mood, sleep, vision, and hearing. 2 - 4 Furthermore, individuals with a history of mTBI are at higher risk for dementia, neurodegenerative diseases, psychiatric illness, and even mortality, indicating long-term progression of subclinical pathology that can manifest later in life. 5 - 7

Despite mTBI lacking obvious clinical neuroimaging findings, making the detection of postinjury neurological changes challenging, there is increasing recognition that advanced neuroimaging techniques are promising biomarkers for its diagnosis, prognosis, and treatment monitoring. 8 , 9 Specifically, diffusion-weighted imaging (DWI) utilizes the diffusion of water within brain tissue to infer microstructural tissue properties. One such advanced technique is diffusion tensor imaging (DTI), which provides a measure of the microstructural integrity of white matter fiber tracts through modeling of the DWI data sets. Within each voxel, DTI estimates specific diffusion variables, including mean diffusivity, fractional anisotropy, axial diffusivity, and radial diffusivity ( Table 1 ). 29 , 30

Previous studies have demonstrated that white matter microstructural integrity, measured by DTI metrics, is perturbed following military-related mTBI. 31 - 35 Additionally, DTI studies of mTBI have reported that microstructural white matter disruptions are associated with neurocognitive and behavioral deficits postinjury. 36 - 38 However, studies of military mTBI have generally yielded varied findings on which white matter tracts are affected and whether fractional anisotropy is increased or decreased following injury. 39 For instance, some studies report lower fractional anisotropy after remote mTBI, 40 , 41 elevated fractional anisotropy, 42 or a lack of significant mTBI effects on fractional anisotropy. 31 , 43 - 46 These inconsistencies may be attributed to the variability in the mechanism (ie, different cellular alterations) and etiology of mTBI at different time points postinjury.

DTI metrics represent basic mathematical descriptions of diffusion that lack structural specificity and do not directly correspond to biophysically meaningful parameters of the underlying tissue. DTI assumes Gaussian diffusion within a single microstructural compartment and is thus insensitive to the complexity of white matter microstructure that is depicted through non-Gaussian models with multiple compartments. 47 To address this limitation, a neurite orientation dispersion and density imaging (NODDI) model was created to offer more specific indices of tissue microstructure. 48 NODDI leverages recent progress in high-performance magnetic field gradients for magnetic resonance imaging (MRI) scanners that can more specifically probe complex non-Gaussian properties of white matter diffusion ( Table 1 ). A 2022 study 22 on civilian subjects used NODDI to identify longitudinal white matter changes of declining neurite density after mTBI, suggesting axonal degeneration from diffuse axonal injury. The study concluded that NODDI metrics are more sensitive and specific biomarkers than DTI for white matter microstructural changes.

However, further investigation using both DTI and NODDI is needed in military populations to improve the health and well-being of service members at higher risk of TBIs and their associated consequences. To our knowledge, this case-control study is the first to leverage DTI and NODDI to examine subtle white matter neuropathological changes in military service members with mTBI as well as their association with neuropsychiatric symptomology in the chronic phase postinjury. We hypothesize that NODDI would be more sensitive and specific to microstructural changes than DTI and that diffusion metrics would be associated with neuropsychiatric symptoms. By combining advanced neuroimaging techniques and neuropsychiatric data, we aim to gain deeper insights into the underlying brain changes associated with military mTBI, ultimately enhancing our understanding and management of this complex condition.

All participants were US military service members enrolled in the Walter Reed National Military Medical Center institutional review board–approved and HIPAA-compliant Neuroimaging Core project. All participants gave written informed consent. This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Participants were scanned at the National Intrepid Center of Excellence at the Walter Reed National Military Medical Center. Inclusion criteria include active duty status or eligibility for the Defense Enrollment Eligibility Reporting system, age 18 to 60 years, male sex or female sex with no current pregnancy or breastfeeding. Exclusion criteria included patients with TBI unable to consent, actively enrolled in other treatment trials where this study would interfere, a history of prior severe neurologic or psychiatric conditions unrelated to the injury event or deployment (eg, meningioma, bipolar disorder), and patients with metal implants or shrapnel. Patients were targeted for recruitment and consent to the study if they had a history of mTBI (ie, mTBI group) or had no mTBI (ie, noninjured controls). Individuals were included in the mTBI group based on confirmed mTBI diagnosis with a history exceeding 2 years, male sex, and active duty status. Participants in the control group were matched for age, sex, and active duty status. Participants from both groups were excluded if they had incomplete PCL-C survey, DTI, or NODDI data. Diagnosis of TBI is described in eMethods in Supplement 1 .

The assessment of commonly affected neuropsychiatric domains after mTBI involved self-report surveys administered prior to the scan. These surveys included the PTSD Checklist–Civilian version (PCLC-C), 49 Neurobehavioral Symptom Inventory (NSI), 50 Generalized Anxiety Disorder-7 (GAD-7), 51 and Patient Health Questionnaire-9 (PHQ-9). 52 The PCL-C is a 17-item measure modeled after the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) ( DSM-IV-TR ) 53 symptom criteria for PTSD. Three cluster scores corresponding to the DSM-IV-TR symptom criteria were calculated: criterion B (reexperiencing cluster), criterion C (avoidance cluster), and criterion D (hyperarousal cluster). The NSI is a 22-item measure designed to evaluate self-reported postconcussion symptoms, such as headache, balance issues, and nausea, rated on a 5-point scale. A total score was obtained by summing the ratings for the 22 items, and 4 cluster scores were calculated as outlined by Vanderploeg and colleagues 54 : vestibular, somatosensory, cognitive, and affective clusters. The GAD-7 is a self-report survey consisting of 7 items designed to assess the severity of generalized anxiety disorder symptoms in individuals over the past 2 weeks. The PHQ-9 is a self-report questionnaire comprising 9 items used to measure the severity of depression symptoms and aid in diagnosing depressive disorders. While participants in both the mTBI and control groups completed the PCL-C, only patients with mTBI completed the NSI, GAD-7, and PHQ-9 surveys.

All subjects were scanned on a 3T MR750 scanner (General Electric) equipped with a 32-channel phased array head radiofrequency coil (MR Instruments). Whole-brain diffusion and structural MRI were obtained. Head motion was represented by framewise displacement measures of diffusion MRI (dMRI) 55 and images were preprocessed with the protocol discussed in eMethods in Supplement 1 .

DTI scalar images (ie, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) were created from dMRI with b-values between 0 and 1000 seconds/mm 2 using the log-signal in 2 steps implemented in MRtrix3. 56 Weighted least-squares with weights based on the empirical signal intensity followed by iterated weighted least-squares with weights determined by the signal predictions from the previous iteration using unconstrained optimization were applied to reconstructed DTI maps. NODDI parameters were calculated using the open-source tool AMICO, 57 which yielded maps of intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) for each participant. 48

In a region-of-interest (ROI) analysis, the fractional anisotropy data were warped to the common FMRIB58 fractional anisotropy template in MNI152 standard space using the symmetric image normalization method implemented in the ANTs package 58 using FMRIB Software Library’s toolbox tract-based spatial statistics (TBSS), a mean fractional anisotropy image was generated from all participant scans in this common space, creating a mean fractional anisotropy white matter skeleton representing common tracts across the entire group and thresholded at above 0.2 to exclude voxels containing gray matter and partial volume effects. The aligned fractional anisotropy volume was projected onto the skeleton by filling it with fractional anisotropy values from the nearest relevant tract center. Output images and the 0.2-thresholded skeleton were visually inspected for accuracy. The same nonlinear warping and skeleton projection steps were then applied to other whole brain mean diffusivity, radial diffusivity, axial diffusivity, ICVF, ODI, and ISOVF maps.

White matter main ROIs were examined by utilizing the Johns Hopkins University (JHU) ICBM-DTI-81 white matter Labeled Atlas 59 in the standard MNI152 space. The JHU-ICBM-DTI-81 white matter labels atlas contains 46 white matter labels (eTable 1 in Supplement 1 ). To analyze these fasciculi, binary mask images corresponding to each tract were used to mask individual skeletonized maps that had been previously registered to the MNI (Montreal Neurological Institute) standard space. Regional values represented by the average voxel value within the selected JHU white matter tract masks were computed for each participant across all generated DTI and NODDI parameter maps.

All statistical analyses were performed using SPSS Statistics version 24.0 (IBM Corp) and R package 4.2.2 (R Project for Statistical Computing). Unpaired 2-sample t tests were used for demographic analysis between groups. χ 2 tests compared the proportion of counts in each military-related category between groups with the expected proportions and the null hypothesis of equal proportions in each group. To compare DTI and NODDI parameters between mTBI and control groups, a generalized linear model (GLM) analysis was conducted with covariates of age and mean framewise displacement followed by nonparametric permutation test and randomization test (eMethods in Supplement 1 ). Variance inflation factor (VIF) was computed to assess the severity of multicollinearity in the OLS regression analysis. 60 Finally, we performed a sensitivity analysis by comparing the variances between full and reduced OLS models and calculating the standardized regression coefficients (SRC), a global sensitivity indices based on linear or monotonic assumptions in the case of independent factors, 61 , 62 and the Johnson indices, indices for correlated input relative importance by R 2 decomposition for linear regression models (eMethods in Supplement 1 ). 63 , 64 The dichotomous receiver operating characteristic (ROC) curve analysis is described in eAppendix in Supplement 1 . A 2-tailed P value at .05 was considered statistically significant.

A total of 98 study participants were included (all male; mean [SD] age, 40.0 [5.2] years); 33 participants had no history of mTBI (mean [SD] age, 39.1 [5.6] years) and 65 participants had a history of mTBI (mean [SD]age, 40.6 [5.0] years) ( Table 2 ). Participants with a history of mTBI had significantly fewer education years compared with those in the control group (mean [SD] education, 14.7 [2.2] years vs 16.3 [2.8] years; P  = .006). A significantly greater proportion of participants in the control group were in the Army compared with those in the mTBI group (22 of 33 [67%] vs 15 of 65 [23%]; P  < .001). A significantly higher proportion of participants with mTBI were enlisted (53 of 65 [82%] vs 17 of 33 [52%]; P  = .002). The mean (SD) mTBI count was 2.1 (1.4), with a mean (SD) time since the most recent injury being 14.2 (9.3) years. Most of the mechanisms causing mTBI were attributed to impacts (24 [37%]) and falls (20 [31%]). Additionally, 9 injuries (14%) resulted from blasts, 10 (15%) from motor vehicle accidents, 1 (2%) from gunshot wounds, and 1 (2%) from various other causes.

Compared with the control group, participants with mTBI history had significantly higher PCL-C total scores (mean [SD] score, 40.9 [11.3] vs 19.0 [3.8]; P  < .001). The mTBI group had a mean (SD) NSI total score of 36.1 (12.4), a somatosensory subscore of 8.4 (4.4), an affective subscore of 12.1 (4.6), a cognitive subscore of 9.1 (3.0), and a vestibular subscore of 3.4 (2.0). The majority of participants with mTBI history had moderately severe (20 participants [31%]) and severe (20 [31%]) anxiety as indicated by the GAD-7 scores as well as moderate (25 [39%]), moderately severe (6 [9%]), and severe (4 [6%]) depression as indicated by the PHQ-9 scores (eTable 2 in Supplement 1 ). Three service members with mTBI (4.6%) did not have NSI scores, which were replaced by imputation using R MICE. NSI, GAD-7, and PHQ-9 were not obtained in healthy controls.

There was no significant group difference of dMRI framewise displacement. This suggests participants with mTBI history had no greater head motion than controls during MRI examination.

ROI analyses using GLMs with age as a covariate revealed widespread differences in DTI and NODDI metrics in various white matter regions ( Table 3 ). Notably, more NODDI metrics were significantly different between control and mTBI groups compared with DTI metrics. Diffusion metrics of ROIs with the highest effect sizes between mTBI and control groups included ICVF of the right corticospinal tract (CST) (β = −0.029, R 2  = 0.136; P  < .001), ODI of the left posterior thalamic radiation (PTR) (β = −6 × 10 −3 , R 2  = 0.253; P  < .001) and ODI of the left uncinate fasciculus (UNC) (β = 0.013, R 2  = 0.125; P  < .001).

When assessing the association with neuropsychiatric symptoms, NSI cognitive subscores were associated with fractional anisotropy of the left UNC (β = 5.4 × 10 −3 ; P  = .003); PCL-C total scores were associated with ISOVF of the genu of corpus callosum (β = 4.3 × 10 −4 ; P  = .01); PCL-C C avoidance subscores were associated with ODI of the left fornix (crus) and stria terminalis (β = 1.2 × 10 −3 ; P  = .02). VIF, an index measuring how much the variance of an estimated regression coefficient is increased because of collinearity, of all models were less than 1.2 ( Table 4 ). Sensitivity analysis of the 3 regression models revealed that the full model (3 independent variables) explained the variances of diffusion metrics better than those of the reduced model (2 independent variables) with an SRC of 0.335, 0.266, and 1.000, and R 2 of 0.091, 0.067, and 0.867 (Johnson indices) for NSI cognitive, PCL-C total scores and PCL-C C avoidance subscores, respectively (eTable 4 in Supplement 1 ). ROC curve analysis is available in eResults in Supplement 1 .

This case-control study investigated diffusion parameters of white matter in military service members with and without remote mTBI. To the best of our knowledge, this is the first study to report white matter microstructural changes indicated by DTI and NODDI metrics using an ROI-based approach in the chronic phase of mTBI among military service members. Our study supports previous evidence that mTBI can have long-term effects on white matter microstructure and neuropsychiatric symptoms related to PTSD, postconcussion syndrome, anxiety, and depression. 65 - 68

The ROI analysis yielded extensive white matter alterations in the mTBI group that were also linked to neuropsychiatric symptoms. Notably, the analysis revealed DTI and NODDI trends of increased anisotropic and parallel diffusion, implicating mechanisms of inflammation, glial cell activation, and tissue scarring or reorganization. 69 , 70 For example, there was increased fractional anisotropy and axial diffusivity, as well as decreased ODI in the left PTR. It is often assumed that lower fractional anisotropy values may correspond to a reduction of the white matter microstructural integrity. 71 However, emerging evidence suggests that higher fractional anisotropy and axial diffusivity values can be attributed to factors such as cytotoxic edema during the acute phase following injury 72 - 74 as well as glial scarring and a manifestation of recovery and/or compensation in the chronic phase, 69 , 72 , 74 - 76 or simply in the voxels with less fiber crossings. In these conditions, the interpretation of higher fractional anisotropy values as solely indicative of increased white matter integrity may not hold true. Some studies indicated that astrocytes undergoing structural remodeling postinjury, thereby driving glial scarring, lead to anisotropic tissue microstructure causing an increase in fractional anisotropy. 69 , 70 , 77 Notably, a 2011 study 69 performing a histological analysis showed that glial fibrillary acidic protein (GFAP), which is a marker for gliosis, was significantly positively correlated with fractional anisotropy and axial diffusivity. Furthermore, decreased mean diffusivity, radial diffusivity, ISOVF, and ODI were observed in the fornix, with ODI values being associated with PCL-C scores. Reduced ISOVF in the corpus callosum was also associated with PCL-C total. Altogether, our findings of compromised white matter in these key tracts complement previous findings that also showed white matter changes in military service members with a remote history of mTBI. 41 , 78

Alternatively, our study also revealed diffusion trends implicating mechanisms of neurodegeneration. For example, decreased ICVF in right and left CST suggests reduced neurite density; reduced fractional anisotropy with increased ODI in the left UNC may suggest axonal degeneration with compensatory neural sprouting. 79 - 81 These findings are consistent with our 2023 study 82 investigating fiber-specific structural changes in a larger cohort of military service members after a remote brain injury. Importantly, fractional anisotropy was significantly reduced in the left UNC and was associated with cognitive-related PCS scores. This anatomically aligns with the significance of UNC in key neural circuitry involving the entorhinal and amygdala, which plays a pivotal role in memory formation and emotion regulation. 83 , 84 Postconcussion symptoms, PTSD symptoms, and neuropsychological function have been shown to be associated with compromised fronto-limbic neurocircuitry in chronic mTBI. 85 , 86

While statistical significance shows that an association exists in a study, effect size indicates the practical significance of a research outcome. R 2 determines the proportion of variance in the dependent variable that can be explained by the independent variable, representing the goodness of fit. Our results show that the ICVF of the right CST had a high Cohen d for group difference but a low R 2 value, while the ODI of left fornix and stria terminalis had a high SRC and R 2 but a relatively low Cohen d . These findings might help explain why diffusion metrics exhibit low dichotomous discrimination.

Lastly, ROC curve analyses indicated that self-reported neuropsychiatric symptoms were more effective in distinguishing between the mTBI and control groups compared with imaging metrics, which did not provide significant discriminatory power. Particularly, PTSD symptoms were successful in classifying participants with mTBI history from controls in this patient population. Prior studies have highlighted the increased risk of comorbid PTSD and mTBI among military service members compared with civilians. 87 - 90 This emphasizes the importance of assessing PTSD symptoms and associated neuropsychiatric symptoms in the management of military-related mTBI. Indeed, while neuroimaging metrics did not show superior discriminatory ability, they did facilitate the identification of potential lesions associated with neuropsychiatric outcomes, which can be used to predict clinical progression and determine the most suitable treatment approach. 91 , 92

This study had several limitations. This was a cross-sectional case-control study with a relatively limited sample size, which offers only a snapshot of the neural factors associated with neuropsychiatric symptoms in the chronic phase postinjury. Although the sample size was similar to other studies using NODDI to examine mTBI, 22 , 23 , 28 , 93 , 94 further analysis with a larger sample is necessary to validate the findings. Additionally, there were missing clinical data that might have influenced the results, including past medical history, preexisting conditions, medications, treatments, or interventions received. Finally, a causal relationship between white matter microstructural alterations and neuropsychiatric symptom presentation cannot be assumed. Thus, these findings should be considered as suggestive of a relationship that should be replicated in other studies.

In this case-control study of military-related mTBI, our results showed that DTI and NODDI can detect microstructural white matter alterations in the chronic phase of mTBI, implicating inflammatory and neurodegenerative processes. Moreover, our findings suggest that NODDI might offer greater sensitivity than DTI in identifying alterations during the chronic phase. Consequently, combining NODDI with DTI parameters in future research could yield valuable insights. Specifically, our results suggest that mTBI in military service members is characterized by widespread differences in diffusion parameters of white matter tracts important for cognitive and emotional processing, including the corpus callosum, CST, UNC, and fornix. Our findings indicate that DTI and NODDI metrics can provide valuable pathophysiological insights into the long-term neuropsychiatric consequences of mTBI.

Accepted for Publication: February 25, 2024.

Published: April 18, 2024. doi:10.1001/jamanetworkopen.2024.8121

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Kim S et al. JAMA Network Open .

Corresponding Author: Ping-Hong Yeh, PhD, RM1128, Bldg 51, National Intrepid Center of Excellence (NICoE), Walter Reed National Military Medical Center, Bethesda, MD 20914 ( [email protected] ; [email protected] ).

Author Contributions: Drs Kim and Yeh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kim and Yeh contributed equally to this article.

Concept and design: Kim, Ollinger, Yeh.

Acquisition, analysis, or interpretation of data: Kim, Song, Raiciulescu, Seenivasan, Wolfgang, Werner, Yeh.

Drafting of the manuscript: Kim, Yeh.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Kim, Ollinger, Raiciulescu, Yeh.

Administrative, technical, or material support: Song, Seenivasan, Yeh.

Supervision: Ollinger, Wolfgang, Werner, Yeh.

Conflict of Interest Disclosures: None reported.

Funding/Support: This project was funded and partly supported by US Army Medical Research and Materiel Command (USAMRMC) (award No. 203337).

Role of the Funder/Sponsor: The institutions with which the authors of this study are affiliated, including USAMRMC, National Intrepid Center of Excellence, Walter Reed National Military Medical Center, and Uniformed Services University of Health Sciences, played no part in the design or conduct of the study; collection, management, analysis, interpretation of the data, manuscript preparation, nor the decision to submit the manuscript for publication. The manuscript was reviewed and approved by the public affairs official at the Uniformed Services University of Health Sciences.

Disclaimer: The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: The authors would like to acknowledge the efforts of the larger team of research coordinators, technical support, and senior management at the Neuroimaging Section of the Research Department, National Intrepid Center of Excellence (NICoE). Particular thanks to Dr Rujirutana Srikanchanat, PhD, Dr Cheng Guan Koay, PhD, Dr Wei Liu, PhD, Mr Adam Cliffton, BA, Mr Joseph Hennesy, BA, and Ms Rebecca Sandlain, BA, for their assistance in MRI data acquisition (affiliated with NICoE); Dr Gerard Riedy, MD, PhD, Dr Grant Bonavia, MD, PhD, and Dr Treven Pickett, PsyD, for administrative support (affiliated with NICoE); Dr Kimbra Kenney, MD, and Dr Chandler Rhodes, PhD, for administering OSU-TBI identification methods (affiliated with NICoE); Dr Hosung Kim, PhD (affiliated with University of South California), for his discussion of the manuscript, and all the clinicians at the NICoE for their hard work of administering interview and clinical care to all the service member participants. None of the contributors has received any compensation beyond terms of employment.

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Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it.

• Aileen A. Ren
• , Daniel A. Snellings
•  &  Mark L. Kahn

Article | 29 April 2020

Olfactory sniffing signals consciousness in unresponsive patients with brain injuries

Odorant-dependent sniff responses predicted the long-term survival rates of patients with severe brain injury, and discriminated between individuals who were unresponsive and in minimally conscious states.

• , Liron Rozenkrantz
•  &  Noam Sobel

APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

• Axel Montagne
• , Daniel A. Nation
•  &  Berislav V. Zlokovic

Article | 15 April 2020

The gut–brain axis mediates sugar preference

Experiments in mice show that a population of neurons in the vagal ganglia respond to the presence of glucose in the gut and connect to neurons in the brainstem, revealing the circuit that underlies the neural basis for the behavioural preference for sugar.

• Hwei-Ee Tan
• , Alexander C. Sisti
•  &  Charles S. Zuker

Article | 12 February 2020

MAFG-driven astrocytes promote CNS inflammation

Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed.

• Michael A. Wheeler
• , Iain C. Clark
•  &  Francisco J. Quintana

Article | 29 January 2020

ATP13A2 deficiency disrupts lysosomal polyamine export

The lysosomal polyamine transporter ATP13A2 controls the cellular polyamine content, and impaired lysosomal polyamine export represents a lysosome-dependent cell death pathway that may be implicated in ATP13A2-associated neurodegeneration.

• Sarah van Veen
• , Shaun Martin
•  &  Peter Vangheluwe

Article | 20 November 2019

NLRP3 inflammasome activation drives tau pathology

The authors show that NLRP3 inflammasome is activated in microglia of patients with fronto-temporal dementia and in a mouse model of tau pathology, and that the loss of NLRP3 inflammasome function decreases tau pathology and improves cognition in mice.

• Christina Ising
• , Carmen Venegas
•  &  Michael T. Heneka

Article | 07 August 2019

Opposing T cell responses in experimental autoimmune encephalomyelitis

Activated clonally expanded CD4 + T cells display specificity to the myelin peptide MOG, whereas clonally expanded CD8 + T cells depend on T cell receptor recognition of unrelated surrogate peptides and have a regulatory function.

• Naresha Saligrama
•  &  Mark M. Davis

Article | 22 July 2019

Potential roles of gut microbiome and metabolites in modulating ALS in mice

A study of the functional microbiome in a mouse model of ALS shows that several gut bacteria may modulate the severity of the disease.

• Eran Blacher
• , Stavros Bashiardes
•  &  Eran Elinav

Letter | 23 January 2019

Altered human oligodendrocyte heterogeneity in multiple sclerosis

Single-nucleus RNA sequencing analysis identifies different subclusters of oligodendroglia in white matter from individuals with multiple sclerosis compared with controls, and these differences may be important for understanding disease progression.

• Sarah Jäkel
• , Eneritz Agirre
•  &  Gonçalo Castelo-Branco

Letter | 13 December 2018

Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone

Archived vials of cadaveric human growth hormone contain substantial levels of amyloid-β (Aβ) peptides and can seed Aβ plaques in susceptible mice, suggesting that this material could have transmitted Aβ pathology to humans.

• Silvia A. Purro
• , Mark A. Farrow
•  &  John Collinge

Perspective | 21 November 2018

LEDs for photons, physiology and food

This Perspective discusses developments in LED-based solid-state lighting for physiological and agricultural applications, and the anticipated benefits in terms of health and productivity.

• P. M. Pattison
• , J. Y. Tsao
•  &  B. Bugbee

Letter | 07 November 2018

Dopamine enhances signal-to-noise ratio in cortical-brainstem encoding of aversive stimuli

Dopamine in the medial prefrontal cortex modulates behavioural responses to aversive stimuli by increasing the signal-to-noise ratio of neurons projecting to the dorsal periaqueductal grey.

• Caitlin M. Vander Weele
• , Cody A. Siciliano
•  &  Kay M. Tye

Article | 31 October 2018

Targeted neurotechnology restores walking in humans with spinal cord injury

Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

• Fabien B. Wagner
• , Jean-Baptiste Mignardot

Letter | 01 August 2018

Human glioblastoma arises from subventricular zone cells with low-level driver mutations

Human neural stem cells from the subventricular zone are identified as the cells of origin that contain the driver mutations for glioblastomas.

• , Jeong Eun Lee
•  &  Jeong Ho Lee

Review Article | 16 May 2018

New approaches for brain repair—from rescue to reprogramming

• Roger A. Barker
• , Magdalena Götz
•  &  Malin Parmar

Letter | 21 February 2018

The cryo-electron microscopy structure of huntingtin

The structure of huntingtin in complex with an interactor is determined to an overall resolution of 4 Å, paving the way for improved understanding of the cellular functions of this protein.

• , Bin Huang
•  &  Stefan Kochanek

Article | 21 December 2017

Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease

Deposition and spreading of amyloid-β pathology in mice requires binding to microglia-released ASC specks.

• Carmen Venegas
• , Sathish Kumar

Letter | 30 August 2017

A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease

Braf  V600E expression in resident macrophage progenitors leads to clonal expansion of ERK-activated microglia, which causes synaptic and neuronal loss in the brain and results in lethal neurodegenerative disease in adult mice.

• Elvira Mass
• , Christian E. Jacome-Galarza
•  &  Frederic Geissmann

Letter | 12 April 2017

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

Antisense oligonucleotides against ATXN2 improved motor neuron function and restored firing frequency in cerebellar Purkinje cells in mouse models of spinocerebellar ataxia type 2.

• Daniel R. Scoles
• , Pratap Meera
•  &  Stefan M. Pulst

Letter | 04 January 2017

Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes

Structural differences in 40- and 42-residue-long amyloid-β fibrils seeded in vitro from the cortical tissue of patients with different clinical subtypes of Alzheimer’s disease suggest that different fibril structures form in different disease variants and with different peptide lengths.

• , Wai-Ming Yau
•  &  Robert Tycko

Letter | 09 November 2016

A brain–spine interface alleviating gait deficits after spinal cord injury in primates

A wireless brain–spine interface is presented that enables macaques with a spinal cord injury to regain locomotor movements of a paralysed leg.

• Marco Capogrosso
• , Tomislav Milekovic

Brief Communications Arising | 13 July 2016

Collinge et al . reply

• John Collinge
• , Zane Jaunmuktane
•  &  Sebastian Brandner

Article | 30 March 2016

Astrocyte scar formation aids central nervous system axon regeneration

Sustained delivery of axon-specific growth factors not typically present in spinal cord lesions allows for robust axonal regrowth only if the astrocytic scar is present—a result that questions the prevailing dogma and suggests that astrocytic scarring aids rather than prevents central nervous system axon regeneration post injury.

• Mark A. Anderson
• , Joshua E. Burda
•  &  Michael V. Sofroniew

Letter | 14 October 2015

Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice

Deep brain stimulation (DBS) of the fimbria–fornix—a region that provides input to the hippocampus—is shown to restore hippocampus-dependent memory and hippocampal long-term potentiation and neurogenesis in a mouse model of Rett syndrome, suggesting that DBS, which is already used in the treatment of several neurological conditions, could be a viable approach to mitigating cognitive impairment in Rett syndrome and other disorders of childhood intellectual disability.

•  &  Jianrong Tang

Brief Communications Arising | 20 May 2015

Wild-type microglia do not reverse pathology in mouse models of Rett syndrome

• , Jan Eike Wegener
•  &  Andrew A. Pieper

Books & Arts | 31 March 2010

Lost curve hits a nerve

• Alison Abbott

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UC experts present at national neurology conference

University of Cincinnati researchers will present abstracts at the American Academy of Neurology annual meeting 2024, April 13-18 in Denver, Colorado.

Two-component treatment leads to improvement for patients

Hani Kushlaf, MD. Photo/University of Cincinnati.

Late-onset Pompe disease (LOPD) is a rare, inherited genetic disease caused by the accumulation of glycogen, the body’s stored form of glucose, in muscles and other organs. Left untreated, the muscle weakness it causes can lead to the loss of the ability to walk and breathing impairment.

A research team led by UC’s Hani Kushlaf, MD, looked at the effect of a two-component enzyme replacement therapy (ERT) of drugs cipaglucosidase and miglustat (cipa+mig) compared to a single ERT drug, alglucosidase alfa (alg) and a placebo. UC researchers participated in the Phase 3 trials that led to the Food and Drug Administration approval of both ERT regimens.

“The research question was to look at the magnitude and practical significance of the effect of cip+mig versus alg using patient data from the PROPEL trial on outcomes that included motor function, pulmonary function, muscle strength, biomarkers and patient- and physician-reported quality of life,” said Kushlaf, associate professor and director of Neuromuscular Research and the Neuromuscular Disorders Division in UC’s Department of Neurology & Rehabilitation Medicine in the College of Medicine.

Patients who switched to the dual ERT regimen experienced improvement or stability across the measured outcomes with no worsening of outcomes. Those who remained on the single ERT drug plus placebo experienced worsening or stability across the measured outcomes.

“This analysis highlights the potential of cipaglucosidase+miglustat to become an important treatment option for patients with LOPD, including patients already on enzyme replacement therapy,” Kushlaf said.

This research was sponsored by Amicus Therapeutics, Inc.

Research team learns more about events following immunotherapy treatment

Luca Marsili, MD, PhD. Photo/University of Cincinnati.

Immune checkpoint inhibitors (ICIs), an immunotherapy that activates the body’s immune system to fight cancer cells, has revolutionized cancer treatment. But while boosting anti-tumor immunity, the treatments may cause severe neurological-immune related adverse events. 

“These neurological-immune-related adverse events include meningitis, encephalitis, demyelinating diseases, vasculitis, neuropathy, neuromuscular junction disorders and myopathy,” said Luca Marsili, MD, PhD, movement disorder fellow in the Department of Neurology and Rehabilitation Medicine in the University of Cincinnati College of Medicine.  

Marsili said the frequency of these adverse events, and the best way to manage them, is still largely unknown. 

A team led by Marsili and Alberto Espay, MD, reviewed reported neurological-immune-related adverse events in patients treated with immune checkpoint inhibitors at UC from 2011-2023. They found the adverse events are rare, affecting 28 patients out of 1,677 treated, or 1.66%. 

The adverse events were most often associated with melanoma treatment with pembrolizumab, a common immunotherapy treatment. 

“The adverse events were most expressed as peripheral neuropathies and encephalitis, manifesting early during treatment within a mean of 2.3 months after ICI initiation,” Marsili said. “Most ICIs, 68%, were discontinued, and in only 10.7% of cases they were restarted without complications.” 

Moving forward, the team said further research is needed to determine clinical susceptibility factors and appropriate timing of restarting ICI treatment after discontinuing due to an adverse event. They are also planning to do more detailed demographic and clinical comparisons of the 28 patients identified to have adverse events to see if there are any predictive factors like tumor type, age, sex or ethnicity. 

“This study is part of a broader project in collaboration with the University of Udine in Italy and with the Department of Internal Medicine at UC,” Marsili said. “We would like to gather a high number of participants to assess incidence/prevalence of these adverse events and also to raise awareness among neurologists on how to treat/manage them.”

Safe, effective treatment for Parkinson’s

Alberto Espay, MD. Photo/University of Cincinnati.

Alberto Espay, MD, will present findings recently published in the Lancet Neurology journal that found Parkinson’s disease medication delivered through an infusion pump is safe and effective at reducing symptoms for longer periods of time. 

Parkinson’s symptoms such as tremors, slowness and stiffness are caused by low levels of dopamine in the body. For decades, doctors have treated Parkinson’s by giving patients levodopa, the inactive substance in the brain that once converted makes dopamine.  

“Levodopa is a replacement strategy. We all make levodopa, but Parkinson's patients make less of it,” said Espay, co-principal investigator of the trial, the James J. and Joan A. Gardner Family Center for Parkinson’s Disease Research Endowed Chair in UC’s Department of Neurology and Rehabilitation Medicine and a physician at the UC Gardner Neuroscience Institute.  

Levodopa is most commonly administered orally, but this trial tested continuous, 24-hour levodopa delivery through a subcutaneous infusion pump. A total of 381 patients with Parkinson’s disease in 16 countries enrolled in the trial and were randomized to receive levodopa through the infusion pump or through traditional oral medication. 

The researchers found levodopa delivered through the infusion pump was safe and led to almost two hours a day (1.72) of additional “on time,” or the time when the medication is working and symptoms are lessened, compared to taking levodopa orally. 

“Once approved, this will become an important treatment strategy to consider for patients with Parkinson’s disease experiencing motor fluctuations not adequately controlled with medication,” he said. “Future studies will need to determine the durability of the long-term benefits and whether any safety issues could emerge, as well as how it might compare with deep brain stimulation.”

Impact Lives Here

The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction.  Next Lives Here.

UC research being presented at AAN includes:

• Kushlaf presenting “ Effect Size Analysis of Cipaglucosidase Alfa Plus Miglustat Versus Alglucosidase Alfa in ERT-experienced Adults with Late-onset Pompe Disease in PROPEL .”
• Marsili and Espay presenting “ Neurological Immune-related Adverse Events of Immune Checkpoint Inhibitors: A Single-center Retrospective Study. ” 
• Espay presenting “ Efficacy of ND0612, a 24-hour Subcutaneous Levodopa/Carbidopa Infusion for People with Parkinson’s Disease Experiencing Motor Fluctuations: Subgroup-analyses from a Randomized, Controlled Phase 3 Study .”
• Stacie Demel, DO, PhD, a physician-researcher at the UC Gardner Neuroscience Institute and associate professor of clinical neurology and rehabilitation medicine in UC’s College of Medicine, presenting “ Methylation Patterns Differ Between ICH Cases and Controls .”
• Yang Yu, MD, UC medical resident/fellow, presenting “ Multiple Sclerosis in a Patient with Friedreich's Ataxia .”
• Rhonna Shatz, DO, adjunct associate professor, division director for behavioral neurology, and the Bob and Sandy Heimann Endowed Chair in Research and Education in Alzheimer’s Disease in the UC College of Medicine, presenting “ Identifying a Relationship Between Executive Dysfunction, Poor Sleep Hygiene/Sleep Apnea, and Ventriculomegaly in Cancer-related Cognitive Impairment (CRCI) ”

Featured illustration at top of brain. Photo/iStock/Onurdongel.

• Clinical Research
• Faculty Staff
• College of Medicine
• UC Gardner Neuroscience Institute
• Academic Health Center
• Neurology & Rehabilitation Medicine

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