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Phineas Gage: His Accident and Impact on Psychology

Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

Emily is a board-certified science editor who has worked with top digital publishing brands like Voices for Biodiversity, Study.com, GoodTherapy, Vox, and Verywell.

Author unknown / Wikimedia Commons

• Phineas Gage's Accident
• Change in Personality
• Severity of Brain Damage
• Impact on Psychology

What Happened to Phineas Gage After the Brain Damage?

Phineas Gage is often referred to as the "man who began neuroscience." He experienced a traumatic brain injury when an iron rod was driven through his skull, destroying much of his frontal lobe .

Gage miraculously survived the accident. However, his personality and behavior were so changed as a result of the frontal lobe damage that many of his friends described him as an almost different person entirely. The impact that the accident had has helped us better understand what the frontal lobe does, especially in relation to personality .

At a Glance

In 1848, Phineas Gage had a workplace accident in which an iron tamping rod entered and exited his skull. He survived but it is said that his personality changed as a result, leading to a greater understanding of the brain regions involved in personality, namely the frontal lobe.

Phineas Gage's Accident

On September 13, 1848, 25-year-old Gage was working as the foreman of a crew preparing a railroad bed near Cavendish, Vermont. He was using an iron tamping rod to pack explosive powder into a hole.

Unfortunately, the powder detonated, sending the 43-inch-long, 1.25-inch-diameter rod hurling upward. The rod penetrated Gage's left cheek, tore through his brain , and exited his skull before landing 80 feet away.

Gage not only survived the initial injury but was able to speak and walk to a nearby cart so he could be taken into town to be seen by a doctor. He was still conscious later that evening and able to recount the names of his co-workers. Gage even suggested that he didn't wish to see his friends since he would be back to work in "a day or two" anyway.

The Recovery Process

After developing an infection, Gage spent September 23 to October 3 in a semi-comatose state. On October 7, he took his first steps out of bed, and, by October 11, his intellectual functioning began to improve.

Descriptions of Gage's injury and mental changes were made by Dr. John Martyn Harlow. Much of what researchers know about the case is based on Harlow's observations.

Harlow noted that Gage knew how much time had passed since the accident and remembered clearly how the accident occurred, but had difficulty estimating the size and amounts of money. Within a month, Gage was well enough to leave the house.

In the months that followed, Gage returned to his parent's home in New Hampshire to recuperate. When Harlow saw Gage again the following year, the doctor noted that while Gage had lost vision in his eye and was left with obvious scars from the accident, he was in good physical health and appeared recovered.

Theories About Gage's Survival and Recovery

The type of injury sustained by Phineas Gage could have easily been fatal. While it cannot be said with certainty why Gage was able to survive the accident, let alone recover from the injury and still function, several theories exist. They include:

• The rod's path . Some researchers suggest that the rod's path likely played a role in Gage's survival in that if it had penetrated other areas of the head—such as the pterygoid plexuses or cavernous sinus—Gage may have bled to death.
• The brain's selective recruitment . In a 2022 study of another individual who also had an iron rod go through his skull—whom the researchers referred to as a "modern-day Phineas Gage"—it was found that the brain is able to selectively recruit non-injured areas to help perform functions previously assigned to the injured portion.
• Work structure . Others theorize that Gage's work provided him structure, positively contributing to his recovery and aiding in his rehabilitation.

How Did Phineas Gage's Personality Change?

Popular reports of Gage often depict him as a hardworking, pleasant man before the accident. Post-accident, these reports describe him as a changed man, suggesting that the injury had transformed him into a surly, aggressive heavy drinker who was unable to hold down a job.

Harlow presented the first account of the changes in Gage's behavior following the accident. Where Gage had been described as energetic, motivated, and shrewd prior to the accident, many of his acquaintances explained that after the injury, he was "no longer Gage."

Severity of Gage's Brain Damage

Since there is little direct evidence of the exact extent of Gage's injuries aside from Harlow's report, it is difficult to know exactly how severely his brain was damaged. Harlow's accounts suggest that the injury did lead to a loss of social inhibition, leading Gage to behave in ways that were seen as inappropriate.

In a 1994 study, researchers utilized neuroimaging techniques to reconstruct Phineas Gage's skull and determine the exact placement of the injury. Their findings indicate that he suffered injuries to both the left and right prefrontal cortices, which would result in problems with emotional processing and rational decision-making .

Another study conducted in 2004 used three-dimensional, computer-aided reconstruction to analyze the extent of Gage's injury. It found that the effects were limited to the left frontal lobe.

In 2012, new research estimated that the iron rod destroyed approximately 11% of the white matter in Gage's frontal lobe and 4% of his cerebral cortex.

Some evidence suggests that many of the supposed effects of the accident may have been exaggerated and that Gage was actually far more functional than previously reported.

Why Is Phineas Gage Important to Psychology?

Gage's case had a tremendous influence on early neurology. The specific changes observed in his behavior pointed to emerging theories about the localization of brain function, or the idea that certain functions are associated with specific areas of the brain.

In those years, neurology was in its infancy. Gage's extraordinary story served as one of the first sources of evidence that the frontal lobe was involved in personality.

Today, scientists better understand the role that the frontal cortex has to play in important higher-order functions such as reasoning , language, and social cognition .

After the accident, Gage was unable to continue his previous job. According to Harlow, Gage spent some time traveling through New England and Europe with his tamping iron to earn money, supposedly even appearing in the Barnum American Museum in New York.

He also worked briefly at a livery stable in New Hampshire and then spent seven years as a stagecoach driver in Chile. He eventually moved to San Francisco to live with his mother as his health deteriorated.

After a series of epileptic seizures, Gage died on May 21, 1860, almost 12 years after his accident. Seven years after his death, Gage's body was exhumed. His brother gave his skull and the tamping rod to Dr. Harlow, who subsequently donated them to the Harvard University School of Medicine. They are still exhibited in its museum today.

Bottom Line

Gage's accident and subsequent experiences serve as a historical example of how case studies can be used to look at unique situations that could not be replicated in a lab. What researchers learned from Phineas Gage's skull and brain injury played an important role in the early days of neurology and helped scientists gain a better understanding of the human brain and the impact that damage could have on both functioning and behavior.

Sevmez F, Adanir S, Ince R. Legendary name of neuroscience: Phineas Gage (1823-1860) . Child's Nervous System . 2020. doi:10.1007/s00381-020-04595-6

Twomey S. Phineas Gage: Neuroscience's most famous patient .  Smithsonian Magazine.

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Harlow JM. Passage of an iron rod through the head . 1848. J Neuropsychiatry Clin Neurosci . 1999;11(2):281-3. doi:10.1176/jnp.11.2.281

Itkin A, Sehgal T. Review of Phineas Gage's oral and maxillofacial injuries . J Oral Biol . 2017;4(1):3.

de Freitas P, Monteiro R, Bertani R, et al. E.L., a modern-day Phineas Gage: Revisiting frontal lobe injury . The Lancet Regional Health - Americas . 2022;14:100340. doi:10.1016/j.lana.2022.100340

Macmillan M, Lena ML. Rehabilitating Phineas Gage . Neuropsycholog Rehab . 2010;20(5):641-658. doi:10.1080/09602011003760527

O'Driscoll K, Leach JP. "No longer Gage": An iron bar through the head. Early observations of personality change after injury to the prefrontal cortex . BMJ . 1998;317(7174):1673-4. doi:10.1136/bmj.317.7174.1673a

Damasio H, Grabowski T, Frank R, Galaburda AM, Damasio AR. The return of Phineas Gage: Clues about the brain from the skull of a famous patient . Science . 1994;264(5162):1102-5. doi:10.1126/science.8178168

Ratiu P, Talos IF. Images in clinical medicine. The tale of Phineas Gage, digitally remastered . N Engl J Med . 2004;351(23):e21. doi:10.1056/NEJMicm031024

Van Horn JD, Irimia A, Torgerson CM, Chambers MC, Kikinis R, Toga AW. Mapping connectivity damage in the case of Phineas Gage . PLoS One . 2012;7(5):e37454. doi: 10.1371/journal.pone.0037454

Macmillan M. An Odd Kind of Fame: Stories of Phineas Gage . MIT Press.

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By Kendra Cherry, MSEd Kendra Cherry, MS, is a psychosocial rehabilitation specialist, psychology educator, and author of the "Everything Psychology Book."

• Study protocol
• Open access
• Published: 17 November 2020

Case management after acquired brain injury compared to care as usual: study protocol for a 2-year pragmatic randomized controlled superiority trial with two parallel groups

• Annemarie P. M. Stiekema   ORCID: orcid.org/0000-0002-6739-3772 1 , 2 ,
• Christine Resch 2 , 3 ,
• Mireille Donkervoort 4 ,
• Natska Jansen 5 , 6 ,
• Kitty H. M. Jurrius 4 ,
• Judith M. Zadoks 7 , 8 &
• Caroline M. van Heugten 1 , 2 , 3  

Trials volume  21 , Article number:  928 ( 2020 ) Cite this article

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People with acquired brain injury may suffer from cognitive, emotional and behavioural changes in the long term. Continuity of care is often lacking, leading to a variety of unmet needs and hindering psychosocial functioning from the occurrence of brain injury up to years thereafter. Case management aims to prevent (escalation of) problems and to facilitate timely access to appropriate services. In other populations, case management has shown to improve psychosocial well-being. In this study, we aim to evaluate the feasibility of case management after acquired brain injury and its effectiveness and cost-effectiveness, compared to care as usual.

This is a pragmatic randomized controlled superiority trial with two parallel groups and repeated measures in adults with ABI and their family, taking place between November 2019 and December 2021 in three provinces in the Netherlands. Participants will be randomly allocated to either the case management group, receiving case management from hospital discharge up to 2 years thereafter, or the control group, receiving care as usual. Effectiveness will be evaluated every 6 months for 18–24 months by patient-reported psychosocial well-being (Hospital Anxiety and Depression Scale (HADS), Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) restriction subscale and the Life Satisfaction Questionnaire (LiSat)), self-management (Patient Activation Measure (PAM)) and care needs (Longer-term Unmet Needs after Stroke (LUNS)). Family outcomes include self-efficacy (Carer Self-Efficacy Scale (CSES)), caregiver burden (Caregiver Strain Index (CSI)), psychosocial well-being (LiSat, HADS), family needs (Family Needs Questionnaire (FNQ)). Feasibility will be evaluated using qualitative methods, assessing fidelity, dose delivered, dose received, reach, recruitment and context. Cost-effectiveness will be determined by the EQ-5D-3L and service use.

At the moment, there is no integrated health care service for people with acquired brain injury and their family members in the long term. If case management is shown to be feasible and (cost)-effective, it could bridge the gap between patients’ and families’ needs and the available services.

Trial registration

Netherlands Trial Register NL8104 . Registered on 22 October 2019.

Peer Review reports

Administrative information

The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ).

Introduction

Background and rationale {6a}.

Acquired brain injury (ABI) may result from stroke (e.g. ischemic or haemorrhagic disruption of blood flow), traumatic brain injury (e.g. from a fall or a blow to the head), brain disease or hypoxia (e.g. after cardiac arrest or near-drowning). People with ABI often experience physical, communicative, cognitive, emotional or behavioural problems [ 1 , 2 , 3 ]. The persisting nature of these changes poses day-to-day challenges in a variety of life domains, such as work or education, household, social relationships and leisure [ 4 , 5 , 6 ], affecting not only quality of life of people with ABI but that of family members as well, as they may need to take on the role of caregiver [ 3 , 7 , 8 ]. There are ample health care services available for people with ABI, but problems exist with regard to their continuity, accessibility and timing [ 9 , 10 , 11 ]. People with ABI and family members feel ill-prepared for discharge from the hospital or rehabilitation centre and ‘abandoned’ once at home, being left with unmet health, social and vocational needs in the long term [ 10 , 11 ].

The importance of supporting a changed life after ABI is increasingly recognized in clinical guidelines [ 12 , 13 ]. Since there are relatively few methodologically sound studies evaluating longer-term care, the Action Plan for Stroke in Europe and the World Stroke Organization state that the development and evaluation of a ‘seamless, coordinated chain of support’, which includes life after ABI, is a development and research priority [ 14 , 15 ].

The development and research on longer-term care services for ABI falls behind in comparison to populations where the need for long-term support has been recognized for longer, such as dementia, oncology and diabetes. A form of longer-term support for these populations is case management, which focusses on supporting people to adapt to the consequences of their health condition in daily life [ 16 , 17 , 18 , 19 , 20 ]. Case management promotes self-management, which refers to choosing strategies, making decisions and undertaking activities to manage a long-term condition and its consequences [ 21 ]. Case management varies in form and duration. The key element is a professional, the case manager, who serves as a first point of contact for patients and their family, is familiar with their situation, supports independent living and links them to available services in the community [ 22 ]. Case management has a positive impact on well-being in dementia, oncology and diabetes, reducing anxiety and depression and increasing quality of life [ 16 , 17 , 18 , 19 , 20 ]. It may decrease financial strains on healthcare as well; for dementia, costs were reduced by 22–33% when providing case management compared to care as usual [ 23 ].

Case management for ABI has been described in the literature, and commonly involves engagement, assessment, planning, education, training and skills development, emotional and motivational support, advising, coordination and monitoring [ 24 ]. These elements are based on best practice; to the best of our knowledge, no randomized controlled trials on long-term case management for ABI have been undertaken to date. The evidence base so far is weak, with a few relatively old non-randomized studies on case management for traumatic brain injury of too low a quality to draw conclusions on its effectiveness [ 25 , 26 , 27 , 28 , 29 ]. Long-term follow-up did show a positive effect on social activities and depression in stroke in a non-randomized trial [ 30 ] and short-term transitional care interventions also show promising results [ 31 , 32 ]. However, since learning how to live with ABI is a dynamic process with fluctuating needs over the course of several years, 3 to 6-month follow-up in the first year and annual reviews hereafter are necessary [ 14 ]. A methodologically sound investigation of the feasibility and effects in terms of health and costs of such long-term support is called for [ 14 , 15 ]. This article describes the study protocol for a pragmatic randomized controlled trial on long-term case management (18–24 months) for people with ABI and their family.

Objectives {7}

The primary objective is to examine the effectiveness of case management for ABI compared to the care as usual on psychosocial well-being (emotional, participation and quality of life outcomes), self-efficacy and unmet needs. Secondary objectives are to explore cost-effectiveness and cost-utility (the balance of costs and gains in health and well-being) of case management compared to care as usual and to explore feasibility of case management for people with ABI and their family in terms of fidelity, dose delivered, dose received, reach and recruitment within its physical, social and political context. We expect case management to be effective and feasible, and we hypothesize that healthcare costs will rise at first and will be reduced in the long-term.

Trial design {8}

This is a pragmatic prospective randomized controlled superiority trial with two parallel groups and repeated measures. Randomization will be performed as block randomization with a 1:1 allocation.

Methods: participants, interventions and outcomes

Study setting {9}.

Recruitment of people with ABI will take place between November 2019 and July 2020 in three hospitals in the Netherlands: Deventer hospital (Deventer), St. Antonius hospital (Nieuwegein and Woerden) and Flevo hospital (Almere). Hospital staff will recruit people with ABI without further involvement in the study procedures, assessments will take place through home visits, via telephone or by sending questionnaires via mail.

Eligibility criteria {10}

People with abi.

People with ABI are eligible for the trial if they comply with all of the following criteria at hospital discharge:

Acquired brain injury objectified by medical specialist (meningitis, encephalitis, hydrocephalus, subarachnoid hemorrhage, intracerebral or intracranial hemorrhage, ischemic stroke, transient ischemic attack, concussion, contusion, other head trauma).

Aged 18 years or older.

Living in the community prior to the injury.

Discharged home or to a rehabilitation centre after hospital visit/admission.

Sufficient command of the Dutch language to understand study procedures.

Access to a computer and the internet (to use the monitoring tool, see ‘ Intervention description {11a} ’).

Willing and able to give informed consent.

Exclusion criteria for people with ABI are:

A neurodegenerative disorder such as Parkinson’s disease or dementia (because of the progressive course of the disease).

A diagnosis related to neuro-oncology (since an intensive care trajectory is already in place for this group).

Discharge to a nursing home.

Family members

Family members are eligible when they comply with all of the following below. Off note, we speak of family members since usually the partner, a child or a parent is most likely to be the primary caregiver in case the person with ABI needs support, but friends or neighbours can also participate in this role if they are the ones most close to the person with ABI.

The person with ABI is eligible and willing to participate (i.e. family members can only participate if their relative with ABI is participating).

They are (or would be if necessary) the primary informal caregiver; i.e. the person most close the person with ABI.

Access to a computer and the internet (to use the monitoring tool and questionnaires).

Case managers

Health care professionals are eligible for the role of case manager if they have professional experience in caring for people with ABI at bachelors’ level or higher (e.g. social workers, nurses, speech and language therapists and occupational therapists). They need to be available for at least 4–8 h per week for the duration of the project, willing to participate in the case manager training at the beginning of the project and in the monthly supervision meetings, and willing to register and document their case manager activities and experiences for research purposes. A formal application procedure will be followed; candidates are hired based on their resume, motivation and job interview by the project leaders.

Who will take informed consent? {26a}

People with ABI and family members who are willing to participate will be visited at home by a trained research assistant, who will obtain informed consent prior to baseline assessment and after going over the study procedures. In case the home visit cannot take place, study procedures will be explained over the phone and informed consent is obtained by mail.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

On the consent form, participants will be asked if they agree to storage and use of their personal information for future research on brain injury or case management and if they agree to be approached for participation in future studies. By signing the consent form, participants give permission to the use of their data should they choose to withdraw from the study, for the research team to request injury-related information from their medical files and to share data with the regulatory authorities and the clinical research monitor of Maastricht University, where relevant. This trial does not involve collecting biological specimens for storage.

Interventions

Explanation for the choice of comparators {6b}.

Case management is compared to the usual care as this is the current alternative.

Intervention description {11a}

• Case management

The framework

The framework for case management for ABI was developed based on a combination of the taxonomy for case management [ 24 ] and descriptions of case management for dementia in the Netherlands (e.g. [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]), because this form of case management is reasonably well integrated in the Dutch health care system. Such services can serve as a base for care innovations for people with ABI because of the shared focus on supporting people to adapt to the consequences of a disorder or disease in daily life [ 47 ].

Case management aims to support people with ABI and family member’s’ self-management of the consequences of ABI and psychosocial well-being, to prevent (escalation of) problems and to facilitate timely access to appropriate services. We propose the following case management elements:

Monitoring: tracking functioning and well-being of people with ABI and family members. In the present study, a digital monitoring system is used for this purpose (described below).

Identification: identification of questions, problems and needs (based on monitoring) that hinder functioning and well-being at the time they emerge.

Assessment: assessing the nature and severity of the presented problem, burden on and capabilities of the person with ABI and the family member, the role of their social network, making implicit or unmentioned questions and problems explicit, drawing conclusions about the core problem in the individual context.

Information (psycho-education): providing information and education on the (impact of) ABI to assist understanding, information or education related to the question or problem (with a focus on capabilities to self-manage the problems), informing on available care and support services.

Provision of support: guiding decision-making with regard to managing the problem, providing practical or psychosocial support for relatively mild problems (focused on maintaining or improving self-management).

Referral: referring to more specialized care or support for relatively complex problems and guiding decision-making with regard to what available services to use.

Coordination: supporting access to services, facilitating collaboration between different service providers and bringing about appropriate care when this is not available through the regular services.

Case management is person-centred and supposed to follow the ‘stepped care’ and ‘matched care’ principles, starting with the least complex form of care and support that meets the demand for help (stepped care), with the form and intensity individually built around the needs and capabilities of the person with ABI and/or the family member (matched care). Case manager activities may therefore vary from offering a listening ear or providing information and advice, to intensively coordinating longer-lasting specialist care. Case manager involvement also may vary in intensity over time, ranging from only monitoring to more intensive involvement.

Case management activities are community-based; they will take place at peoples’ home or other relevant places such as at work, or over the phone, via video calls or via email. While following the stepped care principle, case managers are flexible in the actions (interventions) they choose based on their own professional expertise, the links they make with available services (e.g. they are independent) and the way they create support when available services do not match people’s needs. Part of this study is mapping actual case manager activities onto the proposed elements and exploring whether this concept should be adjusted based on case manager and participant experiences, in order to move towards a more detailed description of what these elements entail in practice.

Monitoring tool (the ReMinder)

Participants receiving case management will be entered into a digital monitoring tool, called the ReMinder, developed by authors KHMJ and MD. This tool was originally developed to empower people who leave the hospital after a head trauma or stroke and their family to find information and get easy access to care in case of the development of problems caused by the injury on the long term. In the current research project, ReMinder is incorporated within OZO Verbindzorg, an online communication system that links different service providers through an online platform. The participant decides who gets access to the information in their OZO Verbindzorg account. For this project, this concerns sharing responses to the ReMinder questions (see below) with their case manager. Participants are in control of their account and may add other professionals involved in their care. They are in control of what information is shared with whom. All procedures are conducted according to the prevalent laws for personal data and privacy.

People with ABI and family members, each having their own account, will automatically receive an email every 3 months, which allows them to enter the monitoring system and to answer two questions: (1) Do you experience problems as a consequence of brain injury? (2) Are you (Is your loved one) able to do all the things you were (he/she was) doing prior to the brain injury? Both questions can be answered with yes or no. If the participant responds ‘yes’ to question 1 and/or ‘no’ to question 2, they are directed to a 32-item questionnaire asking about functioning in the areas of health, daily life, activities, social contacts and consequences of ABI. This questionnaire was composed by the developer of the ReMinder (authors KHMJ and MD), inspired by the Checklist for Cognitive and Emotional Consequence of Stroke (CLCE-24 [ 48 ]), the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P [ 49 ];), Outcome Questionnaire (OQ-45 [ 50 ];) and the life domains of the ICF: International Classification of Functioning, Disability and Health (ICF-model). Participants fill out the questionnaires as self-report. Family members fill out the questionnaire reporting about the person with ABI and five extra questions about his or her own well-being. In order to facilitate easy access to the case manager, at completion of the 32-item questionnaire participants will be asked if they would like to have contact with the case manager (yes/no). In addition, people with ABI and family members also have the opportunity to ask a question to the case manager directly at any time within the online environment.

The responses are visible to the case manager to keep track of functioning and well-being of the person with ABI. The case manager will contact those participants who explicitly indicate that they would like to get in touch. For participants who do not initiate contact with their case manager themselves, the case manager determines whether to contact the participant after the second time participants have filled out the ReMinder (i.e. 3 months after the first ReMinder questionnaire). The decision to get in touch with the participant will generally be based on whether responses indicate that certain problems have not been resolved (consistently low scores in one or more areas), a deterioration in scores, or profound discrepancies in scores between the person with ABI and their family member.

The case manager

The case manager is a fixed contact person; building a relationship is desirable because of the complexity of learning to live with ABI within the individual context, and to prevent the person with ABI and their family from having to tell their story over and over again. A back-up case manager will be assigned as well, who will be involved when the primary case manager is unavailable and who can serve as a sparring partner for the primary case manager.

The case managers form three teams, one in each region. Teams are composed of professionals from different disciplines and with varying backgrounds; some have been working in clinical/rehabilitation settings, others in community outreach, and their experience with support and treatment approaches may be focused on cure or on care. Two of the teams include a peer support worker.

Case managers will participate in a 4-day training prior to the start of the study. The training has a coaching character, promoting team members to draw upon each other’s knowledge and experience. During the training, case managers learn to see beyond one’s own specific professional discipline, get to know the professional background of the other team members and are coached in learning from each other to best support people with ABI and their family. Regular supervision meetings are organized with case managers within regions at least every 2 months, and between regions twice a year.

Care as usual

The usual care differs depending on the regional structures and collaborations. In all regions, limited structured care is available for people who suffered a stroke, mostly for secondary prevention purposes, with a limited duration of 1 year. No structural care is provided for other types of ABI. People with ABI can make use of different forms of care that may or may not involve professionals with expertise on ABI, such as physiotherapy, occupational therapy or social work, but patients usually need to take initiative to find and access these services either themselves or through their general practitioner.

Criteria for discontinuing or modifying allocated interventions {11b}

By design, case management is a modifiable form of care, as it is about organizing interventions based on the individuals’ needs, strengths, weaknesses and living situation. As described before, this study is of a pragmatic nature, granting case managers the flexibility to act as they see fit to support participants, while providing the least amount of support necessary, to stimulate self-management.

Complete discontinuation of case management will occur on participants’ request. People with brain injury can continue if their family member wishes to stop. Off note, a form of ‘active discontinuation’ occurs when participants do not need any support at a given moment: case managers will then monitor the participants’ well-being via the ReMinder and will be available when questions or problems do occur, but do not reach out otherwise. Following the intention-to-treat principle, participants who choose to withdraw from case management (i.e. the intervention) will still be asked to participated in the study assessments. Outcomes are no longer collected when participants choose to withdraw from the study (i.e. the assessments).

Strategies to improve adherence to interventions {11c}

The ReMinder serves as the basis for case managers to monitor if support is needed; participants will receive reminder emails twice a week until they open the ReMinder questionnaire. When two consecutive ReMinder questionnaires (i.e. 3 months apart) are not filled out, participants will be asked by email whether they have trouble getting access to the system, with filling out the questions or whether there is another reason for not using the ReMinder. If they do not respond to any of these emails, their case manager will reach out to explore the reason for this and to determine if further case manager activities are required. Other elements of case management are not subject to adherence as such.

Relevant concomitant care permitted or prohibited during the trial {11d}

All participants are allowed to receive any form of care that they need. Service use will be measured with a questionnaire. Participants are asked not to participate in any other studies concerning psychosocial or pharmacological care for the duration of this trial.

Provisions for post-trial care {30}

Depending on the results of the study and available funding, case management will be continued or gradually scaled down. In case of continuation, participants in the control condition will have the opportunity to receive case management after the study period.

Outcomes {12}

Effectiveness.

Outcomes measures were chosen according to the aim of case management, which involves the concepts of psychosocial well-being, self-efficacy and (unmet) needs. Assessment will take place at baseline, after 6, 12, 18 and 24 months. The total score of the Hospital Anxiety and Depression Scale (HADS [ 51 ];) will serve as the primary outcome measure, other measures (see below) are secondary outcomes.

Outcomes for people with ABI

Psychosocial well-being will be assessed using the HADS, the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P [ 49 ]) restriction subscale and the Life Satisfaction Questionnaire (LiSat [ 52 ]). The HADS consists of 14 items scored on a 4-point scale ranging from 0 to 3 with varying anchors. Total scores can be calculated for the full scale (primary outcome). The two subscales (anxiety and depression) will also be computed and analysed as secondary outcomes; subscale scores of > 7 suggest the presence of an anxiety disorder or depression. The psychometric quality of the scale is sufficient [ 53 ]. The USER-P restriction subscale consists of 9 items asking about restrictions in vocational, leisure and social activities as a consequence of ABI. Items are rated on a scale from 0 (not possible) to 3 (without difficulty) and a ‘not applicable’ option. The total score ranges from 0 to 100 based on the number of applicable items; higher scores indicate less restrictions in participation. The scale has shown sufficient reliability and validity [ 49 ]. The LiSat assesses various aspects of life satisfaction including life as a whole, self-care management, contacts with friends, vocational, family life, partner relationships, financial situation, leisure situations and sex life. The nine items are scored on a 6-point scale ranging from ‘very dissatisfied’ to ‘very satisfied’. The scale has satisfactory reliability and validity [ 54 , 55 ].

The concept of self-efficacy, one’s confidence in the ability to deal with (health) problems, will be measured as a proxy for self-management, since self-efficacy is a prerequisite for behavioural change. Self-efficacy will be measured with the Patient Activation Measure (PAM [ 56 ];), which is a 13-item instrument assessing self-reported knowledge, skills and confidence for self-management of one’s health or chronic condition. Items are scored on a scale of 0 (disagree strongly) to 4 (agree strongly) and a not applicable option. An algorithm is available to transform the scores on the PAM to different levels of self-management, from ‘disengaged and overwhelmed’ to being their own health advocate. The PAM requires a license and sharing of the de-identified data with Insignia Health. The Dutch version of the PAM has shown moderate test-retest ability ( r  = 0.47) [ 57 ].

Care needs will be assessed with the Longer-term Unmet Needs after Stroke questionnaire (LUNS [ 58 ];). The LUNS consists of 22 items scored with ‘yes’ or ‘no’ and one open ended question on the physical, social, and emotional consequences of stroke. To make the LUNS applicable for people with other types of brain injury, we replaced the word ‘stroke’ by ‘brain injury’ in two items. A validation study of the Dutch version of the LUNS concluded that the scale is reliable and valid [ 59 ]. It should be noted that some items merely express worries or a problem rather than needs (e.g., ‘I am worried that I might fall [again] and this is stopping me from doing my usual things’). Nevertheless, we consider the scale to be the most comprehensive scale to assess care needs in the ABI population available in Dutch.

Family member outcomes

Psychosocial well-being, self-efficacy and (unmet) needs will also be measured in family members. In addition to the HADS and LiSAT, of which a description is provided above, caregiver burden will be assessed within the concept of psychosocial well-being. The Caregiver Strain Index (CSI [ 60 ];) will be used, which consists of 13 items that can be responded to with ‘yes’ or ‘no’ and total scores ranging from 0 to 13; higher scores reflecting higher caregiver burden and substantial burden is indicated by a score of 7 or higher. For people who suffered from stroke, the CSI is the most commonly used scale and recommended in the Dutch stroke care guidelines [ 61 ]. The scale has shown sufficient validity and reliability [ 62 ].

S elf-efficacy will be assessed using the Carer Self-Efficacy Scale (CSES) [ 63 ]. The CSES measures self-efficacy with regard to care management and service use, each in 5 items on a 10-point scale from ‘not at all certain’ to ‘very certain’; higher scores on the CSES indicate higher levels of self-efficacy. Reliability and validity of the scale are sufficient [ 64 ].

Family members’ needs will be assessed with the Family Needs Questionnaire (FNQ [ 65 ]). The scale includes 40 items assessing needs that may arise during acute rehabilitation, soon after discharge and in the long-term after ABI. Subscales include health information, emotional support, instrumental support, professional support, community support network and involvement with care. Family members are asked to indicate the importance of each perceived need and then rate the degree to which the need has been met. The Dutch translation has shown sufficient reliability [ 66 ]. Information on the validity of the translation is not yet available, but the English version has shown to be valid [ 67 ].

Cost-effectiveness and cost-utility

Cost-effectiveness and cost-utility will be determined using the EuroQol (EQ-5D-3L) and a service use questionnaire, included in the assessments on baseline and after 6, 12, 18 and 24 months. The EQ-5D-3L [ 68 ] consists of five questions measuring health status. The dimensions covered are mobility, self-care, daily activities, pain or discomfort, and anxiety or depression. These domains are rated as ‘no problem’, ‘moderate problem’ or ‘unable to do’. The EQ-5D-3L has shown good measurement properties [ 69 ]. Service use will be measured with a self-report cost questionnaire, which was constructed to collect cost data from a societal perspective. It is based on the steps described by Thorn and colleagues [ 70 ] and on the questionnaire used by Rauwenhoff and colleagues [ 71 ].

Feasibility

The assessment of feasibility is of exploratory nature and will be assessed using the process evaluation framework of Saunders, Evans and Joshi [ 72 ]. This involves mapping fidelity (quality), dose delivered (completeness), dose received (exposure), reach (participation rate), recruitment (procedures, maintenance of participant involvement) and context (aspects of the physical, social, and political environment). Data will be collected continuously in the form of registrations by case managers, and focus groups will be held at study end (18–24 months after baseline). Data will primarily be used in a summative and descriptive manner. Quantitative indicators to determine feasibility are:

At least 67% of the participants fills out the ReMinder each wave (every 3 months).

Case managers respond to at least 90% of the times patients the request for contact and contact patients 90% of the times this is indicated by the responses in the ReMinder.

Satisfaction with case management (beyond monitoring) is rated with a 7 or higher on a scale of 1–10.

At least 70% making use of case management (beyond monitoring) would recommend case management to others.

Qualitative indicators are:

Participants and case managers reporting on case management in terms of it being acceptable, feasible and useful.

Participants reporting on case manager activities to match their needs (matched care).

Participants and case managers reporting on increasing support when necessary and taking steps back when possible (stepped care)

Participants reporting on case managers’ expertise and skills, case managers reporting on feeling well-equipped to appropriately support participants’ needs.

Other study parameters

The following demographic and injury-related characteristics will be collected at baseline: date of birth, gender, education, date of most recent ABI, type of most recent ABI, date and type of previous ABI(s), hospital admission (yes/no), length of hospital stay of most recent ABI, referral destination at hospital discharge (home or rehabilitation centre).

Participant timeline {13}

The schedule of enrolment, interventions and assessments can be found in Table  1 . All participants will receive the study questionnaires every 6 months until December 2021. Depending on the time of inclusion (up to June 2020), people with ABI will be followed up for 18 to 24 months. A subsample of people with ABI and family members will be approached for additional participation in focus group interviews, taking place at the end of the study (between October and December 2021).The evaluation form will be sent after 1 year and at the final measurement, which can be 18 or 24 months after baseline assessment depending of the time of enrolment.

Sample size {14}

Power calculation was based on the primary outcome measure Hospital Anxiety and Depression Scale (HADS). A study evaluating a monitoring/psycho-educational intervention in patients with possible ABI due to cardiac arrest showed to be effective in improving both anxiety and depressive symptoms with a group difference on the HADS of 3.25 points, corresponding to Cohen’s d effect size of 0.36 [ 73 ]. With an alpha of .05 and power value of 80%, a sample size of 194 is required to detect such between-group effect in the post-intervention measurement. This number can be adjusted for the correlation between baseline and follow-up data, since baseline measures will be entered in the model as an independent variable, by multiplying the sample size by 1 −  R 2 (R is the population correlation between the dependent variable (post-intervention) and the pre-intervention measurement) [ 74 ]. R is estimated to be at least 0.5, making the sample size 194 × (1 − 0.5 2 ) = 146. Taking a drop-out rate of 30% into account, at least 209 people with ABI should be recruited. For each participating person with ABI, the family member who is or would be acting as the informal caregiver will be asked to be enrolled in the study as well. The number of participating family members will not exceed the maximum of 209.

Recruitment {15}

At each of the three recruiting hospitals, trained hospital staff will select eligible people with ABI from the electronic patient files. The hospital staff explains the aim of the study and the study procedures to the patient and ask whether they have a family member who might be interested in participating as well. When the person with ABI or person with ABI-family-member couple is interested in participation, the hospital staff will send them the study information and notifies the researcher. The researcher will call after a week to clarify any questions patients or family members may have. If they are interested in participating, an appointment will be scheduled with the research assistant to sign informed consent, complete the baseline assessment and perform the randomization. In case the person with ABI is referred to inpatient rehabilitation, the appointment will take place as soon as possible after discharge.

Assignment of interventions: allocation

Sequence generation {16a}.

Participants (people with ABI or people with ABI-family-member couples) will be randomly allocated with a 1:1 ratio to either the case management group or the care as usual group, using a computerized random schedule, in blocks of six. The randomization block size will not be disclosed to the research assistant who enrols and assess participants, to ensure concealment.

Concealment mechanism {16b}

The research assistant will be provided with sequentially numbered, opaque sealed envelopes containing randomization information.

Implementation {16c}

The allocation sequence will be generated by a person who is not involved in the study assessments, using a computerized random number generator ( www.random.org/lists/ ). This person will prepare sequentially numbered opaque envelopes containing the information about the group assignment of the participant and seal and the envelopes. The research assistant, who is blind for the allocation sequence and block size, will enrol participants, open the envelope after baseline assessment is completed and provide participants with the information about treatment allocation.

Assignment of interventions: blinding

Who will be blinded {17a}.

At baseline assessment, group allocation will be unknown to both the research assistant and the participants; treatment allocation takes place after completion of the baseline assessment by a research assistant. If people with ABI wish to be visited at home for the follow-up assessments rather than receiving the questionnaires via mail, they will be visited by a member of the research team who is blind to their treatment allocation. Blinding is not possible for the assessment of feasibility.

Procedure for unblinding if needed {17b}

There are no foreseen circumstances under which unblinding is necessary.

Data collection and management

Plans for assessment and collection of outcomes {18a}.

Several methods will be used to obtain information on the process evaluation outcomes: (1) registration forms for case manager activities, (2) written notes of supervision meetings, (3) responses to the questionnaires and participants’ communication with case managers derived from the ReMinder and the OZO system, (4) evaluation forms after 12 months and at study end for participants (both people with ABI and family members) receiving case management and (5) focus group interviews at study end.

Focus groups

Focus groups will be held to obtain in-depth information on the experiences with receiving case management (for participants) and with delivering case management (for case managers). Focus groups are group interviews (approximately 6 participants each) with a particular subject (or focus), and they make use of social interactions between participants. Focus groups are an ideal method to reveal various perspectives on a topic and to uncover new insights and unanticipated issues [ 75 ]. During the focus groups, a moderator (researcher) will use a discussion guide that will include questions on the topics based on fidelity, dose delivered, dose received, reach, recruitment and context [ 72 ]. The interviews will be audio recorded as well as video recorded, to ensure identification of potentially relevant non-verbal information or cues presented by the participants. A second researcher will take additional notes during the focus group interviews.

People with ABI and family members of the three different regions will be selected to form a sample including a wide range of injury-related characteristics and needs (purposively selected) to participate in focus group interviews at the end of the study period. In each region, one people with ABI focus group and one family member focus group will be planned (six in total). This should be sufficient to achieve saturation, i.e. when no new issues emerge from the last focus group, as research suggests that saturation is usually achieved after the fourth group discussion [ 75 ]. Saturation will be checked after these groups and if necessary, additional focus groups will be planned. Because the case managers form a limited group within the scope of the project (25–30 case managers), we aim to include all case managers in focus groups, divided in 3–4 groups.

Effectiveness and cost-effectiveness

The baseline assessment will be completed no more than 2 months after the visit to or discharge from the hospital or, in case of inpatient rehabilitation following hospital discharge, as soon as possible after they leave the rehabilitation centre. Ideally, assessments take place at the participants’ home, but can take place via telephone or questionnaires may be sent and returned by mail in case home visits are not possible (on time). A trained research assistant will explain the study procedures once more and collect the consent form. During home visits, participants fill out the questionnaires on their own and have the opportunity to ask questions. The research assistant will provide support when necessary, for example by reading the questions and possible answers out loud in case of reading difficulties (a common problem after stroke). Information on gender, educational level and living situation will be collected at baseline; date of birth, type and date of most recent and previous brain injuries and discharge destination will be drawn from hospital records by hospital staff. Follow-up measurements will be mailed to the participants, unless people prefer to be assisted, in which case a research assistant (blind to treatment allocation) will visit them at home.

Plans to promote participant retention and complete follow-up {18b}

Participants will receive a five-euro gift card for each measurement (maximum of 25 euros for the complete study). For participating in the focus groups, they will receive an additional fee of ten euros (gift card).

Data management {19}

Data will be collected on paper and then entered electronically twice by members of the research team; any discrepancies between the two entries will be resolved by the person responsible for the second entry, or by discussion with a third researcher if necessary. There are restrictions in place for entering questionnaire data based on the range of answers. Manual range checks will be performed for demographic information. An audit trail will provide with information on all activities in the electronic database. Access to electronic data is controlled by a password system, and access to original data will be restricted by storing the data in a locked cabinet (see ‘ Confidentiality {27}’).

Confidentiality {27}

Data will be handled confidentially and reporting will be coded. All participants will receive a unique identifier that cannot be used to link the data to an individual subject (i.e. CM001). Collected data and personal information will be stored separately in locked cabinets. The involved researchers from Maastricht University will safeguard the key to the code. Only the national supervisory authorities such as the Inspection for Healthcare and Youth (in Dutch: Inspectie voor Gezondheidszorg en Jeugd) will have access to the data upon request. The handling of personal data will comply with the EU General Data Protection Regulation (GDPR) (in Dutch: AVG), the Dutch Act on Implementation of the General Data Protection Regulation, and the Research Data Management Code of Conduct of Maastricht University. The data will be stored for 15 years after the end of the study.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

There will be no collection of biological specimens.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}.

Multilevel modelling will be used to assess the improvement of case management participants over time compared to care as usual. Primary analysis involves entering time, group and their interaction (exposure) as fixed terms. Separate analyses will be performed to assess 24-month outcomes for the subgroup of participants for whom this data is available. Sensitivity analysis will be performed by extending the resulting models with covariates, controlling for the effects of age, gender and level of education. Covariates will be kept in the model as long as they contribute significantly to the model. Significance of the fixed regression effects will be tested using the appropriate t -test ( α  = .05).

The trial-based economic evaluation will involve a combination of a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA). Effects will be presented as clinical outcomes (i.e. self-efficacy and psychosocial well-being). In these CEAs, the incremental cost-effectiveness ratio (ICER) will be expressed as the incremental costs per point improvement on the primary outcome measure. The primary outcomes measure for the CUA will be quality-adjusted life years (QALYs), based on the EuroQol (EQ-5D-3L). The EQ-5D-3L can distinguish between different health states. For each of the different states, a weight is contributed based on the valuation given by the general population (Euroqol group). These range from 0 (representing death) to 1 (representing full health). Cost-effectiveness evaluations make use of these utilities. In the CUA, the ICER will be expressed as the incremental costs per QALY. This economic evaluation will be performed from a societal perspective, which implies that all relevant costs and outcomes will be considered. The time horizon will be the same period as the follow-up period of the trial.

Total costs will be estimated using a bottom-up (or micro-costing) approach, where information on each element of service used is multiplied by an appropriate unit cost and summed to provide an overall total cost. The economic evaluation will assess not only the intervention costs, but also healthcare costs, patient and family costs, and costs outside the health care sector. For this study, we have developed a cost questionnaire, based on existing questionnaires which will identify all relevant costs aspects.

Despite the usual skewness in the distribution of costs, the arithmetic means will be generally considered the most appropriate measures to describe cost data. In case of skewness of the cost data, non-parametric bootstrapping will be used to test for statistical differences in costs between the case management and care as usual group. The bootstrap replications will be used to calculate 95% confidence intervals (CI) around the costs (95% CI). If cost data are distributed normally, t -tests will be used. The robustness of the ICER will be checked by non-parametric bootstrapping (1000 times). Bootstrap simulations will also be conducted in order to quantify the uncertainty around the ICER, yielding information about the joint distribution of cost and effect differences. The bootstrapped cost-effectiveness ratios will be subsequently plotted in a cost-effectiveness plane, in which the vertical line reflects the difference in costs and the horizontal line reflects the difference in effectiveness. The choice of treatment depends on the maximum amount of money that society is prepared to pay for a gain in effectiveness, which is called the ceiling ratio. Therefore, the bootstrapped ICERs will also be depicted in a cost-effectiveness acceptability curve showing the probability that case management is cost-effective using a range of ceiling ratios.

Registration forms, evaluation forms and written notes of supervision meetings will be analysed descriptively, and focus groups will be analysed qualitatively. Audio and videotapes of all focus group interviews will be transcribed verbatim. Analyst triangulation will be applied [ 76 ]; the transcripts and observations combined with additional notes that will be taken during the focus group interviews will be analysed independently by two researchers using the qualitative analysis software ATLAS.ti (version 7.0). An inductive content analysis approach will be adopted [ 77 ], in which common themes and categories emerge using inductive reasoning and constant comparison. The texts will be thoroughly read and open codes will be applied to describe all aspects of the content [ 78 ]. Codes referring to the same phenomenon will be grouped into categories and these categories will be grouped into higher-order themes. Categories and themes will be combined into general statements to describe the phenomenon [ 77 ]. Discrepancies in coding and interpretation will be discussed in a meeting together with a third researcher to reach consensus regarding the categories and themes. The video recordings will be compared with the written transcripts to be able to identify potentially relevant additional non-verbal information or cues presented by the participants. Quotations will be selected based on representativeness of the emerged themes by the coordinating researcher and verified by the other two researchers.

Demographic and injury-related characteristics will be analysed descriptively.

Interim analyses {21b}

No interim analyses are planned because there are no anticipated risks to participation in this study.

Methods for additional analyses (e.g. subgroup analyses) {20b}

Subgroups will be formed based on type of injury (stroke vs. other types) and severity, for which length of hospital stay will be used as a proxy (based on the distribution of the sample). Even though the subgroups are likely to be too small to draw firm conclusions, we will analyse this exploratively because the usual care for stroke is already better organized than for other types of brain injury (possibly lowering the additional gains of case management over care as usual for stroke compared to other types of brain injury) and because those with moderate to severe ABI may have more to gain from case management than those with mild ABI.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Data will be analysed by the intention-to-treat approach. Sensitivity analysis will be performed with regard to missing data; we will evaluate which of the measured variables are associated with missing outcomes and will include these in the model. Reasons for drop-out or missing assessments will be documented if participants are willing to share this.

Plans to give access to the full protocol, participant level-data and statistical code {31c}

The full protocol, anonymized data set and statistical code will be available on request after the results of the study have been published.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}, principal (cmvh), coordinating investigators (apms; cr interim).

Design of the study;

Preparation of protocol and revisions;

Ethics committee application;

Study planning;

Recruiting, training and supervising research assistants;

Responsible for trial master file;

Provide annual reports to ethics committee;

Data verification;

Publication of study reports;

Project team

Principal (CvH) and coordinating (APMS; CR interim) investigators, overall project leader (JZ), intervention project leader (NJ), ReMinder monitoring tool project leader (KJ, MD)

Agreement of final protocol;

Recruiting hospital staff and assistance with recruiting procedures;

Implementing ReMinder;

Entering participants in case management group into monitoring tool;

Recruitment, training and supervising case managers;

Collecting registrations of case management activities;

Organizing project team meetings.

Composition of the data monitoring committee, its role and reporting structure {21a}

Because of the low burden and minimal risks, no data monitoring committee was appointed.

Adverse event reporting and harms {22}

We will only report those adverse events that are directly related to our study, defined as experiencing negative consequences of case management in terms of psychosocial well-being or self-management that are reported spontaneously by the subject. Due to the non-invasive nature of this study, no experiment-related (serious) adverse events are expected.

Frequency and plans for auditing trial conduct {23}

As this study falls under the scope of the Dutch Medical Research Involving Human Subjects Act (Dutch: wet medisch-wetenschappelijk onderzoek met mensen, WMO), the Clinical Trial Centre Maastricht (Maastricht University) appointed an independent clinical research monitor to the study. This person monitors whether the study is conducted according to the ICH-GCP guidelines and legislation and regulations. For our study, four visits divided over the study period are planned.

Activities of the clinical trial monitor are:

Giving advice regarding laws and regulations;

General control of data collection;

Verification of source documents and CRFs;

Controlling the compliance of laws and regulations;

Complying all protocols;

Checking of informed consents;

Controlling the Trial Master File;

Verifying the reports on adverse events and complications.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

All changes (substantial and non-substantial) made to the study protocol after the favourable opinion was given by the accredited medical ethics committee (Medical Ethics Committee of Maastricht University Medical Center+) will be notified to the medical ethics committee, documented in the trial registration and communicated in the publication of the results of this study.

Dissemination plans {31a}

The results, whether positive or negative, will be disclosed unreservedly and submitted for publication to peer-reviewed scientific journals and presented on national and international conferences and meetings for healthcare professionals and people with ABI.

It is essential that people with ABI are supported in learning how to live with ABI, within the individual context in terms of home, education, work, relationships, stage of life and personal goals [ 14 ]. Creating a continuous chain of support from hospital discharge onwards is high on the agenda of guidelines and action plans for different types of ABI [ 12 , 13 , 14 , 15 ]. Continuous and long-term support is currently lacking, as is evident from numerous studies reporting this an important unmet need for people with ABI and caregivers [ 9 , 10 , 11 ] and the lack of randomized controlled trials on longer-term care. We respond to this issue by developing and evaluating case management for people with ABI and their family members. We will evaluate whether case management for ABI is feasible, effective and cost-effective compared to care as usual with a randomized controlled trial.

Strengths of the study are the pragmatic nature of the study and the long-term follow-up. The follow-up with a maximum of 24 months approximates the time it usually takes for people to regain a balance in their lives [ 10 ]. Furthermore, the pragmatic nature allows us to evaluate case management the way it could be implemented in regular practice. The use of the monitoring tool (the ReMinder) is another strength, as it takes a minimum amount of time and effort to keep track of a large group of people for long periods of time. Finally, the combination of qualitative and quantitative evaluation methods should provide us with rich data on feasibility, effectiveness and cost-effectiveness.

A possible limitation of our study is that for a complete picture of cost-effectiveness and cost-utility of case management, the limits placed on the time frame of our study (18–24 months) will be sufficient to capture a long-term reduction in costs. That is, we expect costs to rise in the first year(s) as case management aims to support in getting timely access to services, while the expected longer-term reduction in costly intensive support may extend our study period. Another possible limitation is that we did not define inclusion criteria with regard to severity of ABI, which means that we will include people with mild ABI who may recover well without support; if this group turns out to be large, they may end up masking effects for the more severe group who benefits from case management. Nevertheless, we deliberately chose to include this group, because care continuity for people experiencing problems after mild ABI is currently missing. Case management could fill this gap; by monitoring people with mild ABI, those with suboptimal recovery can be identified and supported, while those who do fully recover require little case manager time, effort and costs.

By evaluating case management for ABI, this study aims to move forward in bridging the gap between the available care and the needs of people with ABI and their family members. If our study shows promise for case management to be (cost)-effective and feasible, it could be a valuable form of regular care to support people with ABI and their family members in finding a new balance in life.

Trial status

The Medical Ethics Committee of Maastricht University Medical Center+ granted ethics approval of the third version of the protocol on September 17, 2019. The trial was registered at the Netherlands Trial Register (registration number NL8104, https://www.trialregister.nl/trial/8104 ) on October 22, 2019, after which recruitment started. The first person was enrolled on November 25, 2019. Inclusion is currently ongoing and expected to be completed in September 2020.

Abbreviations

Cost-effectiveness analysis

Confidence interval

Carer Self-Efficacy Scale

Caregiver Strain Index

Cost-utility analysis

Family Needs Questionnaire

General Data Protection Regulation

Hospital Anxiety and Depression Scale

Incremental cost-effectiveness ratio

Life Satisfaction Questionnaire

Longer-term Unmet Needs after Stroke

Patient Activation Measure

Quality-adjusted life years

Utrecht Scale for Evaluation of Rehabilitation-Participation

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Authors’ contributions {31b}

APMS and CMvH developed the study protocol. CR, MD, NJ, KHMJ and JMZ contributed to the study design and procedures. APMS wrote the first draft of this manuscript. All authors have read and approved the final version of this manuscript.

Competing interests {28}

The authors declare that they have no competing interests.

Funding {4}

This study is supported by a grant from the Dutch Ministry of Health, Welfare and Sport to Stichting InTussen. Both the funder and the sponsor (Maastricht University) had no role in the study design and will have no role in the collection, management, analysis and interpretation of data nor in the decision to submit the report for publication.

Availability of data and materials {29}

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request after publication of the results.

Consent for publication {32}

Not applicable.

Ethics approval and consent to participate {24}

The Medical Ethics Committee of Maastricht University Medical Center+ approved the trial (registration number METC19-040). The study will be conducted according to the principles of the Declaration of Helsinki (World Medical Association, October 2013) and in accordance with the Dutch Medical Research Involving Human Subjects Act (Dutch: WMO). All people with ABI and family members will provide informed consent prior to participation.

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Limburg Brain Injury Center, Maastricht University, Maastricht, The Netherlands

Annemarie P. M. Stiekema, Christine Resch & Caroline M. van Heugten

Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands

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Stiekema, A.P.M., Resch, C., Donkervoort, M. et al. Case management after acquired brain injury compared to care as usual: study protocol for a 2-year pragmatic randomized controlled superiority trial with two parallel groups. Trials 21 , 928 (2020). https://doi.org/10.1186/s13063-020-04804-2

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DOI : https://doi.org/10.1186/s13063-020-04804-2

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Henry Gustav Molaison: The Curious Case of Patient H.M. 

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Henry Gustav Molaison, known as Patient H.M., is a landmark case study in psychology. After a surgery to alleviate severe epilepsy, which removed large portions of his hippocampus , he was left with anterograde amnesia , unable to form new explicit memories , thus offering crucial insights into the role of the hippocampus in memory formation.

• Henry Gustav Molaison (often referred to as H.M.) is a famous case of anterograde and retrograde amnesia in psychology.
• H. M. underwent brain surgery to remove his hippocampus and amygdala to control his seizures. As a result of his surgery, H.M.’s seizures decreased, but he could no longer form new memories or remember the prior 11 years of his life.
• He lost his ability to form many types of new memories (anterograde amnesia), such as new facts or faces, and the surgery also caused retrograde amnesia as he was able to recall childhood events but lost the ability to recall experiences a few years before his surgery.
• The case of H.M. and his life-long participation in studies gave researchers valuable insight into how memory functions and is organized in the brain. He is considered one of the most studied medical and psychological history cases.

Who is H.M.?

Henry Gustav Molaison, or “H.M” as he is commonly referred to by psychology and neuroscience textbooks, lost his memory on an operating table in 1953.

For years before his neurosurgery, H.M. suffered from epileptic seizures believed to be caused by a bicycle accident that occurred in his childhood. The seizures started out as minor at age ten, but they developed in severity when H.M. was a teenager.

Continuing to worsen in severity throughout his young adulthood, H.M. was eventually too disabled to work. Throughout this period, treatments continued to turn out unsuccessful, and epilepsy proved a major handicap and strain on H.M.’s quality of life.

And so, at age 27, H.M. agreed to undergo a radical surgery that would involve removing a part of his brain called the hippocampus — the region believed to be the source of his epileptic seizures (Squire, 2009).

For epilepsy patients, brain resection surgery refers to removing small portions of brain tissue responsible for causing seizures. Although resection is still a surgical procedure used today to treat epilepsy, the use of lasers and detailed brain scans help ensure valuable brain regions are not impacted.

In 1953, H.M.’s neurosurgeon did not have these tools, nor was he or the rest of the scientific or medical community fully aware of the true function of the hippocampus and its specific role in memory. In one regard, the surgery was successful, as H.M. did, in fact, experience fewer seizures.

However, family and doctors soon noticed he also suffered from severe amnesia, which persisted well past when he should have recovered. In addition to struggling to remember the years leading up to his surgery, H.M. also had gaps in his memory of the 11 years prior.

Furthermore, he lacked the ability to form new memories — causing him to perpetually live an existence of moment-to-moment forgetfulness for decades to come.

In one famous quote, he famously and somberly described his state as “like waking from a dream…. every day is alone in itself” (Squire et al., 2009).

H.M. soon became a major case study of interest for psychologists and neuroscientists who studied his memory deficits and cognitive abilities to better understand the hippocampus and its function.

When H.M. died on December 2, 2008, at the age of 82, he left behind a lifelong legacy of scientific contribution.

Surgical Procedure

Neurosurgeon William Beecher Scoville performed H.M.’s surgery in Hartford, Connecticut, in August 1953 when H.M. was 27 years old.

During the procedure, Scoville removed parts of H.M.’s temporal lobe which refers to the portion of the brain that sits behind both ears and is associated with auditory and memory processing.

More specifically, the surgery involved what was called a “partial medial temporal lobe resection” (Scoville & Milner, 1957). In this resection, Scoville removed 8 cm of brain tissue from the hippocampus — a seahorse-shaped structure located deep in the temporal lobe .

Bilateral resection of the anterior temporal lobe in patient HM.

Further research conducted after this removal showed Scoville also probably destroyed the brain structures known as the “uncus” (theorized to play a role in the sense of smell and forming new memories) and the “amygdala” (theorized to play a crucial role in controlling our emotional responses such as fear and sadness).

As previously mentioned, the removal surgery partially reduced H.M.’s seizures; however, he also lost the ability to form new memories.

At the time, Scoville’s experimental procedure had previously only been performed on patients with psychosis, so H.M. was the first epileptic patient and showed no sign of mental illness. In the original case study of H.M., which is discussed in further detail below, nine of Scoville’s patients from this experimental surgery were described.

However, because these patients had disorders such as schizophrenia, their symptoms were not removed after surgery. In this regard, H.M. was the only patient with “clean” amnesia along with no other apparent mental problems.

H.M’s Amnesia

H.M.’s apparent amnesia after waking from surgery presented in multiple forms. For starters, H.M. suffered from retrograde amnesia for the 11-year period prior to his surgery.

Retrograde describes amnesia, where you can’t recall memories that were formed before the event that caused the amnesia. Important to note, current research theorizes that H.M.’s retrograde amnesia was not actually caused by the loss of his hippocampus, but rather from a combination of antiepileptic drugs and frequent seizures prior to his surgery (Shrader 2012).

In contrast, H.M.’s inability to form new memories after his operation, known as anterograde amnesia, was the result of the loss of the hippocampus.

This meant that H.M. could not learn new words, facts, or faces after his surgery, and he would even forget who he was talking to the moment he walked away.

However, H.M. could perform tasks, and he could even perform those tasks easier after practice. This important finding represented a major scientific discovery when it comes to memory and the hippocampus. The memory that H.M. was missing in his life included the recall of facts, life events, and other experiences.

This type of long-term memory is referred to as “explicit” or “ declarative ” memories and they require conscious thinking.

In contrast, H.M.’s ability to improve in tasks after practice (even if he didn’t recall that practice) showed his “implicit” or “ procedural ” memory remained intact (Scoville & Milner, 1957). This type of long-term memory is unconscious, and examples include riding a bike, brushing your teeth, or typing on a keyboard.

Most importantly, after removing his hippocampus, H.M. lost his explicit memory but not his implicit memory — establishing that implicit memory must be controlled by some other area of the brain and not the hippocampus.

After the severity of the side effects of H.M.’s operation became clear, H.M. was referred to neurosurgeon Dr. Wilder Penfield and neuropsychologist Dr. Brenda Milner of Montreal Neurological Institute (MNI) for further testing.

As discussed, H.M. was not the only patient who underwent this experimental surgery, but he was the only non-psychotic patient with such a degree of memory impairment. As a result, he became a major study and interest for Milner and the rest of the scientific community.

Since Penfield and Milner had already been conducting memory experiments on other patients at the time, they quickly realized H.M.’s “dense amnesia, intact intelligence, and precise neurosurgical lesions made him a perfect experimental subject” (Shrader 2012).

Milner continued to conduct cognitive testing on H.M. for the next fifty years, primarily at the Massachusetts Institute of Technology (MIT). Her longitudinal case study of H.M.’s amnesia quickly became a sensation and is still one of the most widely-cited psychology studies.

In publishing her work, she protected Henry’s identity by first referring to him as the patient H.M. (Shrader 2012).

In the famous “star tracing task,” Milner tested if H.M.’s procedural memory was affected by the removal of the hippocampus during surgery.

In this task, H.M. had to trace an outline of a star, but he could only trace the star based on the mirrored reflection. H.M. then repeated this task once a day over a period of multiple days.

Over the course of these multiple days, Milner observed that H.M. performed the test faster and with fewer errors after continued practice. Although each time he performed the task, he had no memory of having participated in the task before, his performance improved immensely (Shrader 2012).

As this task showed, H.M. had lost his declarative/explicit memory, but his unconscious procedural/implicit memory remained intact. Given the damage to his hippocampus in surgery, researchers concluded from tasks such as these that the hippocampus must play a role in declarative but not procedural memory.

Therefore, procedural memory must be localized somewhere else in the brain and not in the hippocampus.

H.M’s Legacy

Milner’s and hundreds of other researchers’ work with H.M. established fundamental principles about how memory functions and is organized in the brain.

Without the contribution of H.M. in volunteering the study of his mind to science, our knowledge today regarding the separation of memory function in the brain would certainly not be as strong.

Until H.M.’s watershed surgery, it was not known that the hippocampus was essential for making memories and that if we lost this valuable part of our brain, we would be forced to live only in the moment-to-moment constraints of our short-term memory .

Once this was realized, the findings regarding H.M. were widely publicized so that this operation to remove the hippocampus would never be done again (Shrader 2012).

H.M.’s case study represents a historical time period for neuroscience in which most brain research and findings were the result of brain dissections, lesioning certain sections, and seeing how different experimental procedures impacted different patients.

Therefore, it is paramount we recognize the contribution of patients like H.M., who underwent these dangerous operations in the mid-twentieth century and then went on to allow researchers to study them for the rest of their lives.

Even after his death, H.M. donated his brain to science. Researchers then took his unique brain, froze it, and then in a 53-hour procedure, sliced it into 2,401 slices which were then individually photographed and digitized as a three-dimensional map.

Through this map, H.M.’s brain could be preserved for posterity (Wb et al., 2014). As neuroscience researcher Suzanne Corkin once said it best, “H.M. was a pleasant, engaging, docile man with a keen sense of humor, who knew he had a poor memory but accepted his fate.

There was a man behind the data. Henry often told me that he hoped that research into his condition would help others live better lives. He would have been proud to know how much his tragedy has benefitted science and medicine” (Corkin, 2014).

Corkin, S. (2014). Permanent present tense: The man with no memory and what he taught the world. Penguin Books.

Hardt, O., Einarsson, E. Ö., & Nader, K. (2010). A bridge over troubled water: Reconsolidation as a link between cognitive and neuroscientific memory research traditions. Annual Review of Psychology, 61, 141–167.

Scoville, W. B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions . Journal of neurology, neurosurgery, and psychiatry, 20 (1), 11.

Shrader, J. (2012, January). HM, the man with no memory | Psychology Today. Retrieved from, https://www.psychologytoday.com/us/blog/trouble-in-mind/201201/hm-the-man-no-memory

Squire, L. R. (2009). The legacy of patient H. M. for neuroscience . Neuron, 61 , 6–9.

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Olfactory function after mild traumatic brain injury in children—a longitudinal case control study

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Janine Gellrich, Claudia Zickmüller, Theresa Thieme, Christian Karpinski, Guido Fitze, Martin Smitka, Maja von der Hagen, Valentin A Schriever, Olfactory function after mild traumatic brain injury in children—a longitudinal case control study, Cerebral Cortex , Volume 34, Issue 4, April 2024, bhae162, https://doi.org/10.1093/cercor/bhae162

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The prevalence of posttraumatic olfactory dysfunction in children after mild traumatic brain injury ranges from 3 to 58%, with potential factors influencing this variation, including traumatic brain injury severity and assessment methods. This prospective longitudinal study examines the association between mild traumatic brain injury and olfactory dysfunction in children. Seventy-five pediatric patients with mild traumatic brain injury and an age-matched healthy control group were enrolled. Olfactory function was assessed using the Sniffin’ Sticks battery, which focuses on olfactory threshold and odor identification. The study found that children with mild traumatic brain injury had impaired olfactory function compared with healthy controls, particularly in olfactory threshold scores. The prevalence of olfactory dysfunction in the patient group was 33% and persisted for 1 yr. No significant association was found between traumatic brain injury symptoms (e.g. amnesia, loss of consciousness) and olfactory dysfunction. The study highlights the importance of assessing olfactory function in children after mild traumatic brain injury, given its potential impact on daily life. Although most olfactory dysfunction appears transient, long-term follow-up is essential to fully understand the recovery process. The findings add valuable insights to the limited literature on this topic and urge the inclusion of olfactory assessments in the management of pediatric mild traumatic brain injury.

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Traumatic Brain Injury Rehabilitation Case Study

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TBI rehabilitation case is a case example of traumatic brain injury (TBI) using neuropsychological (NP) and neurological evaluations and follow-ups to assist the patient in helping her reach her long-term rehabilitation goals. The largest obstacles to achieving success included the patient’s defensiveness and psychological reactions to her situation, fatigue, and higher-level cognitive challenges which were detected on neuropsychological assessment.

Key Questions

What are the benefits of conducting a neuropsychological examination, and how can this data be used to help the physiatrist manage the overall care?

How can the neuropsychologist and physiatrist collaborate effectively to help the patient reach her neurorehabilitation goals?

This case study helps to demonstrate the value of NP testing in treatment of TBI, as well as the value of establishing a strong collaborative relationship between the neuropsychologist and the physiatrist specializing in brain injury rehabilitation.

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Chapter Review Questions

In this case, the diagnosis of TBI was already known. Given this information, how was it useful to obtain neuropsychological testing data, and how did this guide the treatment recommendations for the patient’s outpatient treatment, particularly given that she appeared so “high-level” and obtained some “average” scores?

Why was it important to recommend that a more comprehensive neuropsychological test be given as opposed to providing a basic mental status examination for this patient? Are there times when administering mental status examinations can be useful?

Why was it important for the physiatrist to have some knowledge on treatment of mood disturbances, and when would it have been a good idea to refer out to a psychiatrist?

How does collaboration with a neuropsychologist help a physician better monitor a patient’s cognitive progress and rehabilitation process? How does it help synergize the management of mood disturbances?

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Backhaus, S.L., Durand-Sanchez, A. (2019). Traumatic Brain Injury Rehabilitation Case Study. In: Sanders, K. (eds) Physician's Field Guide to Neuropsychology. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-8722-1_26

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Lessons of the brain: The Phineas Gage story

Harvard Correspondent

In 1848, an iron bar pierced his brain, his case providing new insights on both trauma and recovery

Imagine the modern-day reaction to a news story about a man surviving a three-foot, 7-inch, 13½-pound iron bar being blown through his skull — taking a chunk of his brain with it.

Then imagine that this happened in 1848, long before modern medicine and neuroscience. That was the case of Phineas Gage.

Whether the Vermont construction foreman, who was laying railroad track and using explosives at the time of the industrial accident, was lucky or unlucky is a judgment that Warren Anatomical Museum curator Dominic Hall puzzles over to this day.

“It is an impossible question, because he was extraordinarily unlucky to have an iron bar borne through his skull, but equally lucky to have survived, on such a low level of care,” said Hall. “We are lucky, to have him.”

Gage’s skull, along with the tamping iron that bore through it, are two of the approximately 15,000 artifacts and case objects conserved at the Warren, which is a part of the Center for the History of Medicine in Harvard’s Francis A. Countway Library of Medicine .

The resultant change in Gage’s personality — when he went from being well-liked and professionally successful to being “fitful, irreverent, and grossly profane, showing little deference for his fellows” and unable to keep his job — is widely cited in modern psychology as the textbook case for post-traumatic social disinhibition.

But as the years have gone by and we’ve learned more about his life, argued Hall, the teachings have changed.

“In 1848, he was seen as a triumph of human survival. Then, he becomes the textbook case for post-traumatic personality change. Recently, people interpret him as having found a form of independence and social recovery, which he didn’t get credit for 15 years ago.”

When Gage died 12 years after the accident, following epileptic seizures, his body was exhumed, while his skull and tamping iron were sent to the physician who had cared for him since the accident, John Harlow. Harlow later donated the items to the Warren, where they have remained for 160 years.

“In many ways, I see Gage similarly to how you would see a portrait of one of the famous professors hanging on the wall — he’s an important part of Harvard Medical School’s identity,” said Hall. “By continually reflecting on his case, it allows us to change how we reflect on the human brain and how we interact with our historical understanding of neuroscience.”

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• Neuroscience

The Neuroscience of Behavior: Five Famous Cases

Five patients who shaped our understanding of behavior and the brain..

Posted January 16, 2020 | Reviewed by Lybi Ma

“Considering everything, it seems we are dealing here with a special illness… There are certainly more psychiatric illnesses than are listed in our textbooks.” —Alois Alzheimer (In: Benjamin, 2018)

Once thought to be the product of demonic possession, immorality, or imbalanced humors, we now know that psychiatric symptoms are often caused by changes in the brain. Read on to learn about the people who helped us understand the brain as the driving force behind our behaviors.

Phineas Gage

In 1848, John Harlow first described the case of a 25-year-old railroad foreman named Phineas Gage. Gage was a "temperate" man: hardworking, polite, and well-liked by all those around him. One day, Gage was struck through the skull by an iron rod launched in an accidental explosion. The rod traveled through the prefrontal cortex of his brain. Remarkably, he survived with no deficits in his motor function or memory . However, his family and friends noticed major changes in his personality . He became impatient, unreliable, vulgar, and was even described as developing the "animal passions of a strong man." This was the first glimpse into the important role of the prefrontal cortex in personality and social behavior (David, 2009; Thiebaut de Schotten, 2015; Benjamin, 2018).

Louis Victor Leborgne

Pierre Broca first published the case of 50-year-old Louis Victor Leborgne in 1861. Despite normal intelligence , Leborgne inexplicably lost the ability to speak. His nickname was Tan, after this became the only word he ever uttered. He was otherwise unaffected and seemed to follow directions and understand others without difficulty. After he died, Broca examined his brain, finding an abnormal area of brain tissue only in the left anterior frontal lobe. This suggested that the left and right sides of the brain were not always symmetric in their functions, as previously thought. Broca later went on to describe several other similar cases, cementing the role of the left anterior frontal lobe (now called Broca’s area) as a crucial region for producing (but not understanding) language (Dronkers, 2007; David, 2009; Thiebaut de Schotten, 2015).

Auguste Deter

Psychiatrist and neuropathologist Aloysius Alzheimer described the case of Auguste Deter, a 56-year-old woman who passed away in 1906 after she developed strange behaviors, hallucinations, and memory loss. When Alzheimer looked at her brain under the microscope, he described amyloid plaques and neurofibrillary tangles that we now know are a hallmark of the disease that bears his name. This significant discovery was the first time that a biological molecule such as a protein was linked to a psychiatric illness (Shorter, 1997; David, 2009; Kalia & Costa e Silva, 2015).

In 1933, Spafford Ackerly described the case of "JP” who, beginning at a very young age, would do crude things like defecate on others' belongings, expose himself, and masturbate in front of other children at school. These behaviors worsened as he aged, leading to his arrest as a teenager . He was examined by Ackerly who found that the boy had a large cyst, likely present from birth, that caused severe damage to his prefrontal cortices. Like the case of Phineas Gage, JP helped us understand the crucial role that the prefrontal cortex plays in judgment, decision-making , social behaviors, and personality (Benjamin, 2018).

HM (Henry Gustav Molaison)

William Scoville first described the case of HM, a 29-year-old man whom he had treated two years earlier with an experimental surgery to remove his medial temporal lobes (including the hippocampus and amygdala on both sides). The hope was that the surgery would control his severe epilepsy, and it did seem to help. But with that improvement came a very unexpected side effect: HM completely lost the ability to form certain kinds of new memories. While he was still able to form new implicit or procedural memories (like tying shoes or playing the piano), he was no longer able to form new semantic or declarative memories (like someone’s name or major life events). This taught us that memories were localized to a specific brain region, not distributed throughout the whole brain as previously thought (David, 2009; Thiebaut de Schotten, 2015; Benjamin, 2018).

Facebook /LinkedIn image: Gorodenkoff/Shutterstock

Benjamin, S., MacGillivray, L., Schildkrout, B., Cohen-Oram, A., Lauterbach, M.D., & Levin, L.L. (2018). Six landmark case reports essential for neuropsychiatric literacy. J Neuropsychiatry Clin Neurosci, 30 , 279-290.

Shorter, E., (1997). A history of psychiatry: From the era of the asylum to the age of Prozac. New York: John Wiley & Sons, Inc.

Thiebaut de Schotten, M., Dell'Acqua, F., Ratiu, P. Leslie, A., Howells, H., Cabanis, E., Iba-Zizen, M.T., Plaisant, O., Simmons, A, Dronkers, N.F., Corkin, S., & Catani, M. (2015). From Phineas Gage and Monsieur Leborgne to H.M.: Revisiting disconnection syndromes. Cerebral Cortex, 25 , 4812-4827.

David, A.S., Fleminger, S., Kopelman, M.D., Lovestone, S., & Mellers, J. (2009). Lishman's organic psychiatry: A textbook of neuropsychiatry. Hoboken, NJ: Wiley-Blackwell.

Kalia, M., & Costa e Silva, J. (2015). Biomarkers of psychiatric diseases: Current status and future prospects. Metabolism, 64, S11-S15.

Dronkers, N.F., Plaisant, O., Iba-Zizen, M.T., & Cabanis, E.A. (2007). Paul Broca's historic cases: High resolution MR Imaging of the brains of Leborgne and Lelong. Brain , 130, 1432–1441.

Scoville, W.B., & Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiat., 20, 11-21.

Melissa Shepard, MD , is an assistant professor of psychiatry at the Johns Hopkins School of Medicine.

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January 30, 2018

How Responsible are Killers with Brain Damage?

Cases of criminal behavior after brain injury raise profound questions about the neuroscience of free will. 

By Micah Johnson

Charles J. Whitman and his wife Kathleen are shown in these family album photos released by Whitman's father, Charles A. Whitman, Jr.

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Charles Whitman lived a fairly unremarkable life until August 1, 1966, when he murdered 16 people including his wife and mother. What transformed this 25-year-old Eagle Scout and Marine into one of modern America’s first and deadliest school shooters? His autopsy suggests one troubling explanation: Charles Whitman had a brain tumor pressing on his amygdala, a region of the brain crucial for emotion and behavioral control.

Can murder really be a symptom of brain disease? And if our brains can be hijacked so easily, do we really have free will?

Neuroscientists are shedding new light on these questions by uncovering how brain lesions can lead to criminal behavior. A recent study contains the first systematic review of 17 known cases where criminal behavior was preceded by the onset of a brain lesion. Is there one brain region consistently involved in cases of criminal behavior? No—the researchers found that the lesions were widely distributed throughout different brain regions. However, all the lesions were part of the same functional network, located on different parts of a single circuit that normally allows neurons throughout the brain to cooperate with each other on specific cognitive tasks. In an era of increasing excitement about mapping the brain’s “connectome,” this finding fits with our growing understanding of complex brain functions as residing not in discrete brain regions, but in densely connected networks of neurons spread throughout different parts of the brain.

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Interestingly, the ‘criminality-associated network’ identified by the researchers is closely related to networks previously linked with moral decision making. The network is most closely associated with two specific components of moral psychology: theory of mind and value-based decision making. Theory of mind refers to the capacity to understand other people’s points of view, beliefs, and emotions. This helps you appreciate, for instance, how your actions would make another person scared or hurt. Value-based decision making refers to the ability to judge the value of specific actions or their consequences. This helps you see not only what the outcomes of your actions will be, but whether those actions and outcomes are good or bad. The letters written by Charles Whitman on the eve of his killing spree provide a chilling window into a mind losing the ability to understand good, bad, and other people: “It was after much thought that I decided to kill my wife, Kathy…I love her dearly, and she has been as fine a wife to me as any man could ever hope to have. I cannot rationally pinpoint any specific reason for doing this.”

This research raises troubling questions about Charles Whitman and the other subjects in the study—and for all of us. If their actions were caused by brain damage and a disrupted neural network, were they acting under their own free will? Should they be held morally responsible for their actions and found guilty in a court of law? Should we see them as patients or perpetrators—or both?

Some scientists have followed cases like Charles Whitman’s down the slippery slope, reaching the most extreme conclusion: that by uncovering the biological causes of behavior, neuroscience shows that “free will, as we ordinarily understand it, is an illusion” .

But these arguments depend on a faulty conception of free will. Free will should not be understood as a mysterious ability to cause actions separate from our brain activity. In fact just the opposite might be true: that free will requires certain connections between our brains and our actions. After all, our brains are the biological basis of our identity, housing our memories, our values, our imagination, our ability to reason—in other words, all the capacities necessary to make choices that are uniquely our own, and to carry out actions according to our own will.

This understanding of free will allows us to ask more sophisticated questions about the connection between the brain and criminal behavior when evaluating cases like Charles Whitman’s. Instead of just pointing to the obvious fact that an action had a neural cause (every action does!), we can ask whether a person’s specific neurologic injury impaired the psychological capacities necessary for free will—imagining possible courses of action, weighing relevant reasons, perceiving the moral features of actions and outcomes, making decisions that align with our values, and controlling behavior against competing impulses.

The specific components of moral psychology disrupted by lesions in the criminality-associated network may indeed interfere with these abilities: value-based decision making and theory of mind are important for grasping the moral impact of our actions and understanding how they will be experienced by other people. If a person has genuine impairments in these capabilities, then they possess only a diminished form of free will. Future research should evaluate more robustly the degree to which these and other psychological capacities are truly impaired in patients with lesions in this network.

When moving from the question of free will to issues of moral responsibility and legal guilt, it is important to evaluate each case in light of the wide array of factors beyond neurologic injury that influence behavior. Previous research has demonstrated that criminal behavior is impacted by genetics , childhood mistreatment , low self-esteem during adolescence , lack of parental support ,  social and economic disadvantage , and racial discrimination . Digging deeper into Charles Whitman’s case, we might wonder whether his extraordinarily strict father, or his fascination with guns as early as age 2, contributed to his later violent turn. The lesson is that human behavior is complex and a brain lesion is neither necessary nor sufficient for criminal behavior: after all, there are nearly 700,000 people living with brain tumors in the US and approximately 800,000 people have strokes every year , but the known cases leading to criminal behavior number in the dozens. Further research would be helpful in determining the likelihood that patients who suffer brain lesions in the ‘criminality-associated network’ actually go on to commit crimes, with the expectation that this kind of impairment will emerge as one of many factors increasing the risk of criminal behavior.

The fact that violence can be a symptom of brain disease shows not that free will is an illusion, but that free will can be injured just like other human abilities. These rare cases of dysfunction allow us to see more clearly that our healthy brains endow us with remarkable capacities to imagine, reason, and act freely.

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First Documented Case of Brain Damage From Fentanyl Inhalation

By Oregon Health & Science University April 29, 2024

Following an episode of severe brain inflammation from fentanyl inhalation, a man successfully recovered with the help of a multidisciplinary team at OHSU, as detailed in BMJ Case Reports . This case serves as a warning about the impact of opioids on society. (Artist’s concept.) Credit: SciTechDaily.com

Case study highlights added danger of illicit fentanyl, especially to first-time users.

The man arrived unconscious and near death.

Previously healthy with no known medical history, the 47-year-old arrived by ambulance to the emergency department at Oregon Health & Science University on February 25, 2023. He was found collapsed in his hotel room, where he was staying during a business trip. As clinicians began administering life-saving treatment, they searched for the cause.

Unprecedented Diagnosis

In a case report published online today (April 29, 2024) in the journal BMJ Case Reports , clinicians laid out the surprising and unprecedented diagnosis: toxic leukoencephalopathy by fentanyl inhalation.

In other words, inhaling fentanyl caused large sections of white matter in the patient’s brain to become inflamed to the point where he had lost consciousness and risked irreversible loss of brain function, or possibly death.

Medical experts had documented previous cases caused by inhaling heroin, but the OHSU patient is believed to be the first documented case involving inhalation of illicit fentanyl. The lead author of the study says it should be taken as a warning about the danger of a substance that is cheap, readily available, and 50 times more potent than heroin.

Societal Impact and Awareness

“Opioid use, especially fentanyl, has become very stigmatized,” said lead author Chris Eden, M.D., now a second-year resident in internal medicine in the OHSU School of Medicine who was part of the patient’s treatment team. “This is a case of a middle-class man, in his late 40s, with kids, who used fentanyl for the first time. It demonstrates that fentanyl can affect everyone in our society.”

Although this is the first documented case, Eden said it’s likely other cases simply weren’t recognized due in part to the fact that relatively little is known about the syndrome’s physiology. In addition, he said hospitals haven’t traditionally included fentanyl in their standard urinalysis drug screens. 

At the same time, fatal and nonfatal overdoses due to fentanyl and other opioids are all too common.

“We know very well the classic opiate side effects: respiratory depression, loss of consciousness, disorientation,” Eden noted. “But we don’t classically think of it causing possibly irreversible brain damage and affecting the brain, as it did in this case.”

Magnetic resonance imaging revealed inflammation in the brain. However, the patient’s lingering loss of consciousness, memory and function could have been due to any number of causes — stroke, carbon monoxide exposure or metabolic disease among them. Ultimately, a nonstandard drug test revealed the presence of fentanyl in his system.

Slow Recovery

Fortunately for the patient, he slowly recovered after 26 days in the hospital, followed by a stay in a skilled nursing facility to help regain his speech and function. He is now home with his family in the Seattle area and back to work. To this day, he has no memory of the episode.

The successful outcome involved wraparound treatment with numerous clinicians and support at Oregon’s academic health center and single largest hospital, all operating with a patient-centered approach.

“This case involved internal medicine, neurology, neuroradiology, and palliative care physicians, in addition to nurses, social workers, discharge planners, physical therapists, dieticians, and pharmacists,” Eden said. “I’m proud of these multidisciplinary teams at OHSU working together to take care of complex patients, both from a medical and social perspective.”

Personal Reflections

Today’s publication in  BMJ Case Reports  also includes a perspective from the patient.

“I have regrets often about what I did to myself, my wife, and my family,” he said. “I’m grateful to all the doctors, nurses, and EMTs who saved my life, and the therapists who got me back to a functioning member of society.”

Reference: “Clinical and neuroradiographic features of fentanyl inhalation-induced leukoencephalopathy” 29 April 2024, BMJ Case Reports . DOI: 10.1136/bcr-2023-258395

In addition to Eden, co-authors include Duna Alkhalaileh, D.O., M.P.H., David Pettersson, M.D., and Alan Hunter M.D., of OHSU; and Asad Arastu, M.D., previously of OHSU and now with Penn Medicine.

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Impact of serum leptin and adiponectin levels on brain infarcts in patients with mild cognitive impairment and Alzheimer's disease: a longitudinal analysis

Affiliations.

• 1 Department of Translational Medical Sciences, "Federico II" University, Naples, Italy.
• 2 Department of Neurosciences, Reproductive and Odontostomatological Sciences, "Federico II" University, Naples, Italy.
• 3 Department of Brain Sciences, Imperial College London, London, United Kingdom.
• 4 Clinica San Michele, Maddaloni, CE, Italy.
• 5 Laboratorio di fisiopatologia del sistema neurovegetativo, Istituti Clinici Scientifici Maugeri Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) - Scientific Institute of Telese Terme, Telese Terme, BN, Italy.
• PMID: 38686200
• PMCID: PMC11056582
• DOI: 10.3389/fendo.2024.1389014

Introduction: The adipokines leptin and adiponectin have been associated with atherosclerosis and the risk of cerebral infarcts. Pre-clinical studies, however, suggest a protective role against ischemic brain damage. In this study we analyzed the relationship between serum leptin and adiponectin levels and the onset or progression of brain infarcts in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Methods: All data were extracted from the ADNI database. The final population included 566 subjects, with 58 healthy controls, 396 MCI and 112 AD. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographics, neuropsychological test results, CSF biomarkers, regional brain metabolism with FDG-PET data and the number of brain infarcts on longitudinal MRI scans were extracted.

Results: Leptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the groups. Multivariate logistic regression analysis at baseline for the presence of brain infarcts showed a predictive value for leptin but not for adiponectin. Multivariate longitudinal analysis showed that age was the only significant predictor of brain infarcts development at 15-year follow-up, while serum leptin and adiponectin levels did not play a role in this population.

Discussion: The evidence on the pathogenetic or protective role of adipokines on ischemic brain damage is mixed. In this MCI and AD population, serum leptin and adiponectin were not associated with the development of brain infarcts; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Keywords: Alzheimer’s disease; MR imaging; adiponectin; brain infarcts; leptin.

Copyright © 2024 Carbone, Bencivenga, Santoro, De Lucia, Palaia, Ercolano, Scognamiglio, Edison, Ferrara, Vitale, Rengo and Femminella.

Publication types

• Research Support, Non-U.S. Gov't
• Research Support, N.I.H., Extramural
• Adiponectin* / blood
• Aged, 80 and over
• Alzheimer Disease* / blood
• Biomarkers* / blood
• Brain Infarction* / blood
• Brain Infarction* / complications
• Brain Infarction* / diagnostic imaging
• Case-Control Studies
• Cognitive Dysfunction* / blood
• Cognitive Dysfunction* / etiology
• Leptin* / blood
• Longitudinal Studies
• Magnetic Resonance Imaging
• Middle Aged
• Adiponectin
• ADIPOQ protein, human
• LEP protein, human

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Shillong, April 30: Inhaling the synthetic opioid fentanyl — approved by the US Food and Drug Administration for use as pain relief and anaesthetic — can cause irreversible brain damage, according to a new study on Tuesday.

Fentanyl is cheap, readily available, and 50 times more potent than heroin, warned doctors in the journal BMJ Case Reports after treating a 47-year-old man found unresponsive in his hotel room after snorting the drug.

“We know very well the classic opiate side effects: respiratory depression, loss of consciousness, disorientation,” said lead author Chris Eden, now a second-year resident in internal medicine at the Oregon Health & Science University

“But we don’t classically think of it causing possibly irreversible brain damage and affecting the brain, as it did in this case,” he added.

The middle-aged man was diagnosed with toxic leukoencephalopathy by fentanyl inhalation, which means the substance caused inflammation and damage to the brain’s white matter. This led to unconsciousness and also to potentially irreversible loss of brain function, or possibly death.

The condition is manifest in various signs and symptoms, the most obvious of which are neurological and behavioural changes, ranging from mild confusion to stupor, coma, and death.

Although the recovery is slow, some people will recover fully, while others will progressively get worse.

In this case, a brain scan revealed white matter inflammation, swelling, and injury in his cerebellum — part of the brain responsible for gait and balance.

The man remained bed-bound for 18 days later and was fed via a tube. Doctors prescribed several different drugs to treat urinary incontinence, kidney injury, cognitive impairment, suspected opioid withdrawal, pain and agitation, and pneumonia.

After 26 days, he underwent rehabilitation, and after another month, he returned home. However, outpatient physiotherapy and occupational therapy continued.

The study reported that it took him almost a year to fully recover and return to work full-time. (IANS)

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After spinal cord injury, neurons wreak havoc on metabolism

Mouse study finds common drug prevents injury effects on fat tissue.

Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study has found.

After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury.

Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems -- in this case, affecting sensory neurons and the abdominal fat tissue to which they're sending signals.

"We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating a chain of reactions -- triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance," said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.

"Through administration of gabapentin, we were able to normalize metabolic function."

The study is published today (April 24, 2024) in Cell Reports Medicine .

Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury. These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.

Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system -- nerve activity known for its "fight or flight" response, but also a regulator of adipose tissue that surrounds the abdominal organs.

Instead, Debasish Roy -- a postdoctoral researcher in the Tedeschi lab and first author on the paper -- decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.

In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons -- without interrupting the sympathetic nervous system.

Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons -- though only in their communication function, not their regrowth or structure -- and in visceral fat tissue. Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue -- which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.

"These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat," Tedeschi said. "A vicious cycle is established -- it's almost like you're pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out."

The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.

"The fat is responding to the presence of CGRP, and it's activating lipolysis," Tedeschi said. "CGRP is also a potent vasodilator, and we saw increased vascularization of the fat -- new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state."

Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin -- which targets alpha2delta1 and its partner, alpha2delta2 -- was a good treatment candidate. Tedeschi's lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.

But in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood -- and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance -- a known side effect of gabapentin.

The team changed drug delivery tactics, starting with a high dose and tapering off -- and stopping after four weeks.

"This way, we were able to normalize metabolism to a condition much more similar to control mice," Roy said. "This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting."

Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.

Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease -- and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.

This work was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institutes of Health, and by the Chronic Brain Injury program at Ohio State.

Co-authors, all from Ohio State, were Elliot Dion, Jesse Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas and Wenjing Sun.

• Nervous System
• Disorders and Syndromes
• Brain Injury
• Neuroscience
• Life Sciences
• Cell Biology
• Molecular Biology
• Adipose tissue
• Diabetes mellitus type 1
• Embryonic stem cell
• Stem cell treatments

Story Source:

Materials provided by Ohio State University . Original written by Emily Caldwell. Note: Content may be edited for style and length.

Journal Reference :

• Debasish Roy, Elliot Dion, Jesse A. Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas, Wenjing Sun, Andrea Tedeschi. α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury . Cell Reports Medicine , 2024; 101525 DOI: 10.1016/j.xcrm.2024.101525

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Strange & offbeat.

Dad who suffered brain injury days after getting COVID vaccine sues AstraZeneca

Jamie Scott alleges the pharmaceutical giant exaggerated the vaccine's effectiveness and downplayed its risks. AstraZeneca denies the claims made against them.

Science correspondent @SkyNewsThomas

Monday 29 April 2024 19:04, UK

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A dad who suffered a brain injury just days after receiving a British-developed COVID vaccine has told Sky News he would never have had the jab if he had known of the risk of rare but serious side effects.

Jamie Scott, who has two young boys and is now unable to work, is suing AstraZeneca for what he says is damage caused by the jab in April 2021.

He alleges the pharmaceutical giant exaggerated the vaccine's effectiveness and downplayed its risks.

AstraZeneca denies the claims made against them.

In his first TV interview, Mr Scott told Sky News: "I took it to protect the elderly people around me.

"AstraZeneca and the government need to explain the risk whenever you take medicine. If there's a risk - I've got a young family - I would never have taken it."

Ten days after having his first dose of the vaccine, Mr Scott woke up with a severe headache, started vomiting and had trouble speaking.

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• Oxford-AstraZeneca vaccine

He was taken to hospital where he was diagnosed with a clot that was stopping blood draining from his brain, as well as a haemorrhage in the brain itself.

He had surgery and was in a coma for just over a month. His wife Kate was told that if he survived he would never be the same again.

Mr Scott now has a poor memory, has trouble reading, writing, listening and speaking, is partially blind in both eyes and suffers from pain and fatigue.

He says he can't drive or play an active part in his boys' lives.

"Everything about me has changed. Everything is difficult," he said.

"I am happy to be alive. But I'm a shadow of what I was and every day is difficult."

There are 51 cases lodged with the High Court with people claiming damage as a result of vaccination. Some are bereaved relatives.

Mr Scott was given a payout of £120,000 from the government's Vaccine Damage Payment (VDP) scheme.

But that comes nowhere near to replacing the career income he would have received as an IT professional.

"If Jamie was in a car crash there would have been insurance to cover the injuries and loss of income," said Mrs Scott.

"We should not have to lose our house, or not be able to afford to fix our cooker when it breaks down or not be able to take the kids on holiday.

"If VDP was reformed, we would not have to litigate."

To be given the full £120,000 payout from the vaccine damage scheme claimants have to be assessed as at least 60% disabled. Those with a lower degree of disability - which can still be life-changing - don't qualify.

The AstraZeneca vaccine was developed by scientists at the University of Oxford. It went through accelerated testing and licensing because of the urgency of the pandemic and was authorised for emergency supply in December 2020.

The government and many doctors assured the public that the vaccine was safe and urged people to take the jab.

But in the spring of 2021, there were reports around Europe of people suffering unusual blood clotting several days after vaccination.

Sarah Moore, a lawyer at Leigh Day Solicitors who is representing Mr Scott and the other claimants, told Sky News: "As early as the beginning of March in 2021, other European countries had withdrawn or suspended this product from the market because they had seen this problem.

"Our argument is that on the date upon which Jamie's vaccine was applied, there was no warning.

"Now, if you are going to take a healthy person and give them any medical product, then generally most people would accept that has to be a warning within the product literature that specifies that risk, particularly when we're talking about the gravity of risk in this context."

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AstraZeneca says it updated product information for the vaccine in April 2021 to reflect the possibility in very rare cases that it could be a trigger for thrombosis with thrombocytopenia syndrome.

In a statement, it said: "Our sympathy goes out to anyone who has lost loved ones or reported health problems. Patient safety is our highest priority and regulatory authorities have clear and stringent standards to ensure the safe use of all medicines, including vaccines.

"From the body of evidence in clinical trials and real-world data, the AstraZeneca-Oxford vaccine has continuously been shown to have an acceptable safety profile and regulators around the world consistently state that the benefits of vaccination outweigh the risks of extremely rare potential side effects."

Read more from Sky News: Man admits killing mobility scooter rider Humza Yousaf resigns as Scotland's first minister

This is not anti-vax – it's about being honest about medicines

Science correspondent

There's no question that what happened to Jamie Scott is an utter tragedy.

He had a great career, two boys and a loving wife. And when his invitation came for the COVID jab he seized the chance to protect his elderly relatives and do his bit to bring the pandemic to an end.

But that was the day that his life was up-ended, suffering what his lawyers say was a catastrophic reaction to the AstraZeneca vaccine.

He has been unable to work since, and probably never will. His wife Kate has given up her job to be his carer.

The Scotts argue that had he been in a car accident the insurers would have settled on a sum that reflected his likely career earnings and the amount of care he needed.

But he has been given just £120,000 from the government's vaccine damage payment scheme. That's the maximum payout.

It is a paltry sum when you are 44 - as he was at the time - with no other source of income and decades of life ahead of you.

Read Thomas Moore's full analysis here

The Department of Health and Social Care said it doesn't comment on ongoing litigation or specific cases.

It added that the AstraZeneca jab hasn't been used in the UK since the start of the booster programme in the autumn of 2021 because alternative mRNA vaccines were shown to be more effective.

However, the vaccine has been widely used around the world. In the first year of use, more than two billion doses were given, saving an estimated six million lives.

At the time of the rollout - and since - there has been a vocal minority of people who campaigned against COVID vaccines.

But Mr and Mrs Scott say they are not anti-vaxxers.

Mrs Scott said: "I would say we are vaccine-hesitant now because if it goes wrong you are left out in the cold.

"There has to be protection for those people who did the right thing when the government said it was safe and effective, time and time again.

"Even now if you try and question that narrative you're shut down and told that's anti-vax - and it just can't be."

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