1. Design and registration

A systematic review of the literature was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The systematic review is a narrative synthesis of studies and registered with Prospero (International Prospective Register of Systematic Reviews–registration number CRD42021224467)

2. Literature search

Initial database searches commenced in September of 2020 and included Embase, Medline, PsycINFO, Psychology and Behavioural Science and Scopus. This was also supported by a search of the first 5 pages of Google scholar. The search was updated in January 2022 and August 2023.

The search was undertaken using keywords and medical subject heading searches (MesH) under the guidance of the university librarian. Boolean Operators “AND” and “OR” were used to combine search terms where appropriate, “OR” was used for within group combinations while “AND” was used for between group combinations. “NOT” was used to eliminate search terms. The search was restricted to studies with human participants and those published in English and employed the following search structure ((brain* N3 (donat* OR bank OR biobank*)) AND (psychological* OR griev* OR dying OR grief OR distress* OR attitude* OR Motivat* OR impact* OR “Informed consent*” OR decision*) AND (famil* OR “loved one” OR “next of kin” OR patient* OR person* OR individual* OR communit* OR donor* OR deceased* OR parent* OR child*). Given the overwhelming abundance of donation and transplantation literature, search exclusions included (NOT “transplantation”, “brain death”, “brain dead”, “renal” and “kidney”).

3. Inclusion criteria

1. Study Design and type: cross-sectional quantitative studies and qualitative studies which included original data under the following categories:
   1. Studies investigating the reactions, perceptions, or experiences with brain donation from the perspective of donors, relatives, next of kin or communities.
   2. Studies exploring societal views of brain donation.
   3. Studies investigating patterns of consent for brain donation and decision-maker motivations.
2. Participants: Studies which documented the perspectives of donors (potential and actual), next of kin, health care practitioners and community members. Potential donors were defined as individuals who were discussing a theoretical participation in or interaction with a brain donation program. Brain donation programs were broadly included across disease types and not limited based on neuro-pathological focus or scientific/clinical question.

4. Exclusion criteria

Methods papers focusing primarily on refinement of biobanking protocols or recommendations for improved consent processes were excluded. Biobank case study papers documenting evolution of procedures were excluded as were papers conducting sentiment or thematic analysis on donors of regenerative tissues for transplantation.

5. Screening

All articles were exported to Endnote 20.3 and duplicates removed following the conclusion of the search process. After deduplication, articles were exported into Covidence for title and abstract screening. Title and abstract screening was completed independently by two reviewers (JRB, CPG) based on the inclusion and exclusion criteria. If the eligibility of the study could not be determined during the title and abstract screening it was included to allow for full-text screening. Full-text screening was completed independently by the same reviewers. Discrepancies were resolved between the two reviewers JRB and CPG with no need for a third reviewer. Reasons for exclusion during the full-text screening were recorded in Covidence.

6. Data extraction

Data extraction was performed independently by two members of the review team JRB and CPG. The reviewers discussed any discrepancies until resolved and did not require a third reviewer to resolve disagreements. The following data were extracted from each of the included studies:

1. Publication details: author, study title, publication, publication year, country of study
2. Study setting: disease type or purpose of brain banking program
3. Sample size: including participant subgroup stratification if present
4. Population: description of study population
5. Study method: Surveys, telephone interviews, focus groups
6. Subgroup: clinicians, potential donors, next of kin (bereaved or prior to donation)
7. Findings/Results: perceptions of harm and perceptions of benefit

7. Quality appraisal

Quality appraisal was conducted by reviewers JRB and CPG using the suite of critical appraisal tools available through the Joanna Briggs Institute. All data types included in this analysis met either the criteria for the ‘Checklist for Analytical Cross-Sectional’ [17] data or ‘Checklist for Qualitative Research’ [18]. This process was carried out independently with two reviewers determining whether a study met or did not meet the eight criteria for the cross-sectional analysis or the ten criteria for qualitative research.

8. Data analysis and synthesis

A reflexive process, caried out by JRB and CPG was used to code and group extracted data. This process was guided by the principles of reflexive analysis as outlined by Braun and Clarke 2020 [19], though it should be noted a full thematic analysis was not employed due to the heterogeneity of the data and diverse methodological approaches. The process began with data familiarisation to emphasise context and setting, systematic data coding (in this case based on language repetition or language redundancy). The initial process involved a focus on identifying common language, themes and experiences to develop a concise picture of perceived harms and benefits shared by respondents throughout the literature. Subsequently the data were re-examined subjectively and with a deductive approach to identify recurring sentiments. This allowed data to be grouped and resulted in a set of codes. This ‘continuum’ approach to data synthesis allowed for an inclusion of the semantic to the latent within the data. Following analysis, data was collated into two tables for ease of interpretation. As per the methodology of Braun and Clarke, researcher subjectivity was employed as a resource for production, not a threat to credibility [19].

Output from systematic search

Fig 1 documents the results of the search and screening process, beginning with a total of 1025 papers and resulting in a final cohort of 40 (Fig 1).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 1. PRISMA guided search strategy.

Fig 1 documents the search strategy employed, capturing both the 2020,2022 and 2023 search periods.

https://doi.org/10.1371/journal.pone.0295438.g001

Table 1 documents publication details, data type, study population, setting sample size and designated subgroup of participants for the 40 included studies.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Included studies.

https://doi.org/10.1371/journal.pone.0295438.t001

Quality appraisal of studies

Table 2 documents the output of the quality appraisal for each of the studies presenting cross sectional quantitative data. Table 3 contains quality appraisal results from those with primarily qualitative data.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Quality appraisal for cross-sectional studies.

https://doi.org/10.1371/journal.pone.0295438.t002

None of the studies presenting cross-sectional data met all 8 criteria, with no study able to employ a standard criterion for measurement. Measurement of exposure was problematic for many studies in that participant exposure and experience of brain donation varied widely. Some studies were able to categorically include participants who had been directly involved in either consenting to a brain donation study or had supported a loved one to donate, while others were collected data from participants based on theoretical scenarios.

One study, Le Bouc 2016, did not identify confounding factors within the data, while three studies Bidaut-Russell 1991, Schnieders 2013 and Angelini 2011 did not clearly include details of their statistical methodology. In two studies, Le Bouc 2016 and Siminoff 2021, inclusion criteria were not outlined or unclear however all provided a clear description of subjects and settings to ensure contextual representation of the data.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Quality appraisal results from those with primarily qualitative data.

https://doi.org/10.1371/journal.pone.0295438.t003

Of the 10 criteria for qualitative studies, 3 were consistently met by all studies: Congruity between research methodology and objectives, adequate representation of participant voices and appropriate conclusions drawn from the interpretation of the data. Of the criteria, a statement locating the researcher culturally or theoretically and consideration of the influence of the researcher on the research were the two requirements most frequently unaddressed with only Moules 2021 and Lambe 2011 providing reference to the role of the researcher and the context or lens through which the researcher was working. Morlett Paredes 2022 did locate the researcher culturally and cite the presence of bi-lingual and bi-cultural researchers, but did not explicitly discuss researcher influence.

Subsequent analysis of the data yielded the commonality with which certain themes or ideas were presented within the literature. Tables 4 and 5 below describe the themes identified and the specific perceived benefits described in relation to each theme.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 4. Perceptions of benefit noted in study.

https://doi.org/10.1371/journal.pone.0295438.t004

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 5. Perceptions of harm noted in study.

https://doi.org/10.1371/journal.pone.0295438.t005

Perceived benefit

As described in Table 4, commonly documented perceived benefits were the benefit to future generations, a desire to aid disease/scientific research, the idea that the donation avoids waste, benefit to medicine in terms of improved treatments and diagnosis and the belief that donation will assist the family by bringing consolation, meaning or aid the grief process for family.

Codes relating to altruism, both as a responsibility and in a wider context were frequently reported, as were codes related to specifically benefiting research, medicine and science. These can be combined to create a wider theme of altruism. Within the category of ‘comfort and consolation’ two codes related to the idea of ‘living on’ are noted, suggesting that this is a theme both in the practical sense of an enduring cell line and also in an existential or sense of legacy. Codes related to avoidance of waste can also be considered in conjunction with those concerning honourable character and organ donation suggesting alluding to themes of purpose and meaning making.

Perceived harm

Of the perceptions of harm, the most commonly documented was a perceived conflict with religious beliefs, that donation would result in damage or disfigurement to the donor, that consent would lead to emotional distress for the NOK at time of autopsy, that consent could lead to discord or objections within the family and that donation would not align with the wishes of the deceased. Codes relating to emotional harm were commonly recorded. The majority of perceived harms were noted to be potential harms or misconceptions and this was true for codes relating to emotional distress, inappropriate motivations, physical harm, suffering. These codes hold relevance for discussions of awareness, education and overcoming cultural barriers.

Inter-group comparisons

Quality appraisal

The data are heterogenous with regard to setting, context, methodology and personal experience. This presented numerous challenges for quality appraisal. None of the cross-sectional studies was able to apply a standard and objective form of measurement, however this is due to an absence of validated tools within the literature. However, when studies present personal insights and depictions of human experience in an emerging area it can be argued that standardised measurement may decrease the richness of the data [58]. It is likely this will be addressed in coming years as work in the area continues. For example, Glaw et al 2009 [13] reported a previously published tool and Garrick et al 2006 [27] piloted a measure.

Surprisingly only two studies assessed with the qualitative quality appraisal tool demonstrated awareness of the role of the researcher. Whether this is a deliberate choice to remove researcher subjectivity, is unclear. Given the well documented value of reflexivity [59], and the distinctly human experience of the subject area, it would be encouraging to see a greater representation of the role of the researcher in future studies.

Perceptions of benefit and harm–variables for consideration

With respect to broad perceptions of benefit, altruistic outcomes were predominant in the literature. We identified two clear altruistic categories, however many others such as ‘benefit to health and medicine’ or ‘helping future generations of family’ can also be seen as having altruistic intent leading to a prevailing theme of altruism. Considerable work has been conducted into the theories of and role of altruism with respect to post-mortem tissue donations, so much so that Quinn et al 2013 suggests it as intrinsic to recruitment strategies [60]. There are three key theories of altruism pertaining to biological donations; pure altruism which refers to donation as a gesture of good will, reciprocal altruism [61] which entails expectations of return for either the donor or the family, and empathy-induced altruism where a shared experience or improvement to the welfare of a group/culture is anticipated [62]. All three of these theories can be identified within the data relating to brain donation however it could be argued that reciprocal and empathy-induced underpin the vast majority of codes identified, particularly with respect to benefit to family, future generations and to those themes categorised as ‘education/information’ and ‘instigating change’.

Interestingly, it could be argued that the data regarding the need to ‘repay’ medical care illustrates a somewhat inverted form of reciprocal altruism whereby donation is an act of reciprocity rather than carried out with anticipated reciprocity. Reciprocal altruism is fraught with ethical pitfalls and as Quinn identifies, can lead to a “web of mutual obligations” whereby a patient may feel obligated to donate due to the efforts of the medical team but also assume that their donation renders researchers obligated to deliver a cure or provide higher level care to surviving family [60]. Perceptions of benefit that are linked with reciprocal altruism while valid and empowering for donors, require careful consideration. Care should be taken to manage expectations during consent to ensure psychosocial benefits to the participant are maximised and unwarranted concerns about potential treatment are not part of the decision-making process.

Both in the oncology and non-oncology settings we coded data relating to ‘living on’ through a donation [11,12,16,31,49]. In a non-oncology space, where sense of self could be clearly associated with brain tissue this appears rational–particularly in light of brain exceptionalism, the notion that the brain holds special significance to sense of self [63]. In an oncology space, however, and particularly where studies may include populations where only malignant tumour was removed, these insights become even more interesting. This is well demonstrated through the unique insights captured by the paediatric oncology studies included in this review. In the work of Moules et al on paediatric cell lines, parents reported being comforted by the knowledge that their child was ‘living on’ in the tumour cell line [11] referencing a sense of connection to the culture. This is a sentiment echoed in numerous other studies, both oncology and non-oncology such as Padoan et al [31] and ties in with broad references throughout the wider brain donation literature to living on and legacy being a primary benefit [11,12,16,31,49].

Somewhat of a misalignment occurs, however, when one juxtaposes the idea of the child ‘living on’ through cell line development with the notion that parents are comforted knowing their child was buried ‘without their tumour’ [12]. This sentiment resonates with the experiences of our study team who operate in a brain cancer context, suggesting that the notion of removing something negative is equally powerful in comforting the bereaved as are promises of creating a legacy. Whether this dichotomy of ‘something antagonistic to excise’ vs ‘something protagonist to treasure and maintain’ is the result of a selective understanding/rationalisation on the part of the individual, or variations in the language used by the consenting team is unclear. This may also be due to variations in tissue collection, namely whether the brain as a whole is removed or a partial tumour. Further work to understand the impact of this variable is required to fully characterise the human experience of brain donation in the paediatric setting but is outside the scope of this review.

While cited as a benefit, recurring references to ‘avoiding waste’[11–13,16,21,24,33,38,39,41,42,44,45,55] are interesting when one considers the harm that could be caused by refusing brain donation. While there are exceptions, broadly speaking, people with a metastatic cancer diagnosis or who have received a systemic form of chemotherapy are unable to donate tissues for transplantation purposes in Australia [64]. Donor families report participating in organ donations can be a resolving factor in grief [65] and it can serve as a way of giving back for the greater good or avoiding waste for donors [66]. If organ donation is perceived as a means of producing hope or ‘good’ from tragedy [67] then it stands to reason that the ineligibility of people with a cancer diagnosis–including those who have consciously consented to organ donor registries–adds to the disappointments felt by patients and their families. In light of this, it’s clear that for many, brain donation for research provides a means from which to restore purpose and meaning and ensure that ‘good’ can come from suffering even when organ donation for transplantation is no longer an option. This is particularly well illustrated by Eatough et al whereby a respondent was comforted by references to ‘harvesting’ brain tissue which resonated with her in terms of her life continuing to be ‘fruitful’ following her death [16]. Further support exists in the paediatric setting with recent discussions proposing that brain donation may actually be seen as a palliative intervention due to the emphasis on legacy and meaning-making [68].

It remains to be seen as to whether the sense of empowerment or comfort is greater for those who have previously been refused organ donation for transplantation due to systemic chemotherapy, such as in a brain cancer diagnosis. That said, it could be suggested by the frequent references to organ donation and association of organ donor status with honourable character [13,16,35,36] that for a committed organ donor who is ineligible to donate, the opportunity to participate in a brain donation study directly influences the human experience of participating–restoring purpose and meaning, particularly for altruistically minded persons.

The data indicate that the primary perception of harm associated with brain donation is an incompatibility with religious beliefs or teachings. The work by Wu et al work explored this in detail with respect to Confucian teachings in Taiwanese culture and the moment the soul is believed to leave the brain [22]. While there may be concerns in religious communities such as Confucians, Shintoists and Orthodox Jews, along with concerns raised by South Asian Islamic scholars, it has been cited that no known religious doctrine formally objects to or prohibits organ donation [69]. The body of evidence examining this subject is almost exclusively in a transplantation context however the findings are transferable when the broad understanding is that consent to organ donation or receipt is not explicitly discussed in sacred texts and therefore left to the conscience of the individual. This has been outlined in the Jehovah Witness faith, a group typically associated with objections to blood transfusions or biological medical interventions [70]. It appears that in many instances the concerns of religious councils against organ donation lie in broader concerns regarding the definition of death and the acceptance of cardio-cessation but not brain death as a legitimate death [71]. This serves as a differentiating factor for post-mortem donations and suggests that those with concerns of post-mortem donations may benefit from improved communication with, and facilitated education from, religious and spiritual leaders.

Many of the perceived harms of brain donation are potential misconceptions with practicalities such as ‘delay to funeral’, fears of ‘disfigurement to donor’ and the concern that the ‘donor might not be dead’ clear examples. The nature of rapid autopsy ensures no delay to funeral arrangements with processes typically completed within 24 hours and the nature of the procedure itself ensures donors are fit for open casket or to be viewed by loved ones with little to no obvious signs of autopsy or physical trauma. Likewise concerns around ‘awake’ or ‘live’ autopsy can be allayed with sufficient education and communication around the necessity for a death certificate and thorough examination by a medical professional. The persistence of these views is unsurprising when one considers Khuta’s data indicating that in a USA movement disorders clinic only 78% of participants had heard of brain donation and only 7.5% of those who were familiar with the concept had received educational material from a health care provider [28]. This indicates the need for improved communications underpinned by extensive stakeholder engagement to ensure educational interventions are appropriate. For example, in the work of Boise [55] and Lambe [43], the perceived harm of inappropriate use of donated tissue is likely grounded in historical cultural abuses and requires far greater consideration than concerns of ‘disfigurement’ identified by Chan et al [41] which can be quite simply allayed.

Future work in the area should also consider the potential harms such as ‘privacy’, ‘confidentiality’ and a ‘restriction of end-of-life choices’. While these harms are not outside the realm of possibility, informed consent processes should detail the safeguards and measures employed by biobanking facilities to mitigate the risks of privacy and confidentiality breaches. Likewise, while the donation process does have logistical and feasibility requirements that could potentially impact end of life decisions, we have shown previously that through planning and informal systems reform, rapid brain tissue donation can be facilitated in a manner consistent with the end of life wishes of the donor–despite geographical or logistical challenges [72]. Crucial to facilitating this is a multi-disciplinary clinical support team, united in supporting the patient to donate once consented however the data collected in this review suggests this may be an enduring challenge for brain donation teams.

This is particularly relevant when one considers the insights unique to health care providers, namely the concern that raising the topic of donation may lead patients to view clinicians as having a greater interest in research than in patient care. Within the wider literature search, no data was obtained on health care providers perceptions of benefit. This is reinforced by Le Bouc et al’s findings that the major limiting factor in consent to brain donation is clinicians being unwilling to raise the idea [30]. Whether health care providers do not perceive value in brain donation cannot be answered in the absence of data, however we can infer from broader biobanking data that in many cases health care providers do perceive value, but feel ill equipped to enter into conversations regarding consent [73]. This finding appears relevant and aligns with concerns that an improper or mismanaged conversation could damage the doctor patient relationship and lead to further harm, again reinforcing the importance of education–not only for patients and families but for health care providers. As such, it can be inferred that the relationship between donor and health care provider, and the degree to which the health care provider is supported and equipped to facilitate brain donation conversations is highly influential for the lived experience of brain donation.

Limitations

Heterogeneity in study type and population is a limitation to this study, introducing confounding variables such as donor cognitive ability, level of dependence on carers, frequency of interaction with the health service, duration of illness and imminence of mortality. Geographic variability is also highly pertinent and a considerable limitation to this study when one considers the diversity in international health care systems and the variability in HCP relationships to patient, resource scarcity/availability and integrated psychosocial support.