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The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration. Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.

Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients. Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1) immunization to affect longevity. In addition, among CD4(+) T cells in ALS patients, levels of CD45RA(+) (naïve) T cells were diminished, while CD45RO(+) (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+)CD25(+) T regulatory cells (Treg) or CD4(+)CD25(-) T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage. A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

Diet is increasingly recognized as a potential upstream modulator of the gut-brain axis (GBA) through its effects on the microbiome, microbial metabolites, and host immune and endocrine responses. The GBA is a complex, bidirectional network connecting the gastrointestinal tract and central nervous system, with diet influencing microbial community structure and metabolic output. Plant-based diets, such as Mediterranean and MIND, have been associated with increased production of anti-inflammatory microbial metabolites and improved barrier function, while high calorie/low nutrient diets are often linked to increased immune activation and barrier dysfunction. However, while microbial metabolites, especially short-chain fatty acids, indoles, bile acids, and isothiocyanates, have been proposed as mediators of neuroprotective effects, their role in neurodegenerative diseases remains an area of active investigation, with evidence largely derived from preclinical and associative human studies. Cruciferous vegetables, especially broccoli sprouts, are an emerging focus of research for their bioactive compound sulforaphane, which activates Nrf2-centered cytoprotective pathways. Animal and early human studies suggest sulforaphane can improve cognitive and behavioral outcomes, though larger clinical trials are needed. Personalized, microbiota-targeted dietary interventions may offer scalable strategies for managing neuroinflammatory and neurodegenerative conditions, and we emphasize the need for integrated research across diet, microbiome, and brain health.

Multiple Sclerosis (MS) can be a severely disabling condition that leads to various neurological symptoms. A Brain-Computer Interface (BCI) may substitute some lost function; however, there is a lack of BCI research in people with MS. Present BCI designs have also overlooked the unique pathological changes associated with MS and have not considered needs of users within their home environments. To progress this research area effectively and efficiently, we aimed to evaluate user needs and assess the feasibility and user-centric requirements of a BCI for people with MS. We hypothesised that (i) people with MS would be interested in adopting BCI technology and (ii) those with reduced independence would prefer a higher-performing invasive BCI. We conducted an online survey of people with MS to describe user preferences and establish the initial steps of user-centred design. The survey aimed to understand their interest in BCI applications, bionic applications, device preferences, and development considerations and related these to symptoms and assistance needs. We demonstrated widespread interest for BCI applications in all stages of MS, with a preference for a non-invasive (n = 12) or minimally invasive (n = 15) BCI over carer assistance (n = 6). Descriptive analysis indicated that level of independence did not influence preference towards the higher performing but highly invasive BCI. The needs of end users reported in this study are crucial for efficient development of BCI systems that can be effectively translated into the home environment. Considering the potential to enhance independence and quality of life for people living with MS, the results emphasise the importance of user-centred design for future advancement of BCIs that account for the unique pathological changes associated with MS.

Studying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyze the brain's response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brain's perturbation response or “cortical excitability” could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalized epilepsy (GGE), with ( n = 10) and without ( n = 10) PPR, and patients with psychogenic non-epileptic seizures (PNES; n = 10), compared to resting controls ( n = 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.

Background Early intervention in cerebral palsy could improve motor outcome but is only possible following early identification of those affected. There is a need for training of healthcare professionals (HCPs) in early detection of atypical motor development. We developed a video-based e-learning course - Training in Early Detection for Early Intervention (TEDEI) - to address this need. We evaluated whether participation in the course improved knowledge and changed behaviour of HCPs. Methods Participants were 332 HCPs (38% physiotherapists, 35.8% occupational therapists), predominantly UK-based (83.7%). Analysis of training effects used mixed methods and followed Kirkpatrick’s model, first assessing “Reaction” through a feedback questionnaire involving Likert scale and free text responses ( n  = 141). “Learning” was assessed through multiple choice questions (MCQs): all 332 HCPs completed a pre-course quiz of 6 MCQs followed by the course, then a 16 item post-course quiz including the 6 pre-course questions. “Behaviour” was assessed through in-depth qualitative interviewing of 23 participants. Results “Reaction”: TEDEI was found to be effective, engaging and well structured. “Learning”: Scores improved significantly between the pre-course and post-course quiz, median improvement 1/6 (z = 5.30, p  < 0.001). HCPs also reported a perceived improvement in their knowledge, confidence and ability. “Behaviour”: HCPs could see how TEDEI would improve their clinical practice through having an assessment framework, ways of working better with parents, and developing observational skills useful for tele-health assessments. Conclusion Our brief e-learning course on early detection for early intervention was viewed positively, improved knowledge and showed potential for positive changes in practice. Kirkpatrick’s model provided a useful framework for undertaking this evaluation.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.

Microglial neuroinflammatory responses affect the onset and progression of Parkinson’s disease (PD). We posit that such neuroinflammatory responses are, in part, mediated by microglial interactions with nitrated and aggregated α-synuclein (α-syn) released from Lewy bodies as a consequence of dopaminergic neuronal degeneration. As disease progresses, secretions from α-syn-activated microglia can engage neighboring glial cells in a cycle of autocrine and paracrine amplification of neurotoxic immune products. Such pathogenic processes affect the balance between a microglial neurotrophic and neurotoxic signature. We now report that microglia secrete both neurotoxic and neuroprotective factors after exposure to nitrated α-syn (N-α-syn). Proteomic (surface enhanced laser desorption–time of flight, 1D sodium dodecyl sulfate electrophoresis, and liquid chromatography-tandem mass spectrometry) and limited metabolomic profiling demonstrated that N-α-syn-activated microglia secrete inflammatory, regulatory, redox-active, enzymatic, and cytoskeletal proteins. Increased extracellular glutamate and cysteine and diminished intracellular glutathione and secreted exosomal proteins were also demonstrated. Increased redox-active proteins suggest regulatory microglial responses to N-α-syn. These were linked to discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation. Inhibition of cathepsin B attenuated, in part, N-α-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration.

Incentivizing the development of interdisciplinary scientific teams to address significant societal challenges usually takes the form of pilot funding. However, while pilot funding is likely necessary, it is not sufficient for successful collaborations. Interdisciplinary collaborations are enhanced when team members acquire competencies that support team success. We evaluated the impact of a multifaceted team development intervention that included an eight-session workshop spanning two half-days. The workshop employed multiple methods for team development, including lectures on empirically supported best practices, skills-based modules, role plays, hands-on planning sessions, and social interaction within and across teams. We evaluated the impact of the intervention by (1) asking participants to assess each of the workshop sessions and (2) by completing a pre/postquestionnaire that included variables such as readiness to collaborate, goal clarity, process clarity, role ambiguity, and behavioral trust. The content of the team development intervention was very well received, particularly the workshop session focused on psychological safety. Comparison of survey scores before and after the team development intervention indicated that scores on readiness to collaborate and behavioral trust were significantly higher among participants who attended the workshop. Goal clarity, process clarity, and role ambiguity did not differ among those who attended versus those who did not. Multicomponent team development interventions that focus on key competencies required for interdisciplinary teams can support attitudes and cognitions that the literature on the science of team science indicate are predictive of success. We offer recommendations for the design of future interventions.

Employee well-being is a pressing concern, particularly in healthcare professions where workers face greater exposure to adverse environments. This concern informed the central research question for this study: How do employees describe their perceptions of organizational support and offerings related to well-being provided by a nonprofit mental health organization? A generic qualitative method was chosen to collect data on participants' individualized perceptions, feelings, and experiences. Ten participants were recruited from a U.S.-based nonprofit mental health organization. During data collection, participants completed virtual interviews that were designed with semi-structured interview guide aligning to the central research question, allowing them to provide rich, detailed insights in their own words. The theoretical foundation for this research and study was organizational support theory. Thematic analysis resulted in five key themes: (a) mental health employees’ perceptions of organizational support and well-being offerings involved flexibility; (b) mental health employees’ perceptions of organizational support involved feeling valued by leaders; (c) mental health employees’ perceptions of organizational support and well-being had a practical and an emotional impact; (d) Mental health employees’ perceptions of organizational support and well-being offerings involved togetherness; and (e) mental health employees’ perceptions of organizational support involved recognition. The findings revealed that when employees receive support and relevant offerings, they experience perceived organizational support (POS) and respond positively, benefiting their organizations. At the same time, in many organizations, supervisors struggle to promote workplace well-being due to intense workloads, uncertainty about advocating for well-being, lack of support, and limited access to resources. Given the rapid changes many organizations face, recognition and feedback have become a priority in addressing employee well-being. Simple yet impactful health and wellness initiatives, such as mindfulness practices, can build character, skills, and awareness, facilitating positive changes.