A possible multimodal dietary and nutritional, exercise, meditation and cognitive remediation intervention for severe neuropsychiatric illness including cognitive impairment. Due to the complex multifactorial etiology of severe mental illness with cognitive impairment, a multimodal intervention that targets multiple restorative factors including neuroplasticity, neurotransmission, brain energetics and implementing cognitive remediation with health affirming lifestyle shifts such as meditation could be a potentially valuable therapeutic option to improve quality of life. Previous literature [1] suggests there may be a synergistic effect between the various interventions (aerobic exercise, ketogenic interventions, other nutritional factors/diet) that may alleviate cognitive impairment. The strategy devised by Cunnane et al. (2022) was used as a starting point with the interventions centred around: - diet [maintaining dietary ketosis 0.5 < ~3 mmol/L through a ketogenic diet] -supportive nutritional supplementation (multivitamin, fish oil, vitamin D, acetyl-L-carnitine) - vigorous daily exercise greater than 45min of jogging/exercise bike - daily mindfulness, loving-kindness and gratitude meditations - online cognitive training (HappyNeuron) first centred on intensive attentional training and memory skills, later targeting a more diverse range of cognitive skills - Adding positive health affirming activities to the day ie. learning, gardening, social activities and reading Figure 1. The proposed, potentially synergistic, interventions 1 Dietary ketosis and it's neuropsychiatric benefits: Ketone bodies provide an alternative energy source to the brain when carbohydrates are limited and fat, via beta-oxidation to eventual ketone bodies, becomes the predominate fuel for brain energy supply [2]. Ketone bodies have an array of benefits on the brain in addition to their role as an energy source, including upregulation of neurotrophic factors, mitochondrial function, modulation of neurotransmission, insulin-sensitising, anti- inflammatory, oxidative stress reducing and epigenetic actions. One ketone body, β-hydroxybutyrate (BHB) has been shown to be be a major contributor of the beneficial effects of aerobic exercise, particularly related to the upregulation of BDNF [3]. The literature on dietary ketosis as an intervention for neuropsychiatric illness encompasses a diverse range of positive findings, including in depression [4], psychotic disorders [5] and cognitive impairment [6, 7]. There are diverse effects on mood, psychiatric symptomatology and cognition seen. In particular, cognition seems to be beneficially impacted by dietary ketosis with some studies noting improvements with dietary interventions, including with supplemental medium-chain triglycerides (MCTs) [8] which act as a ketogenic source even in the adequate supply of glucose. Also, the brain energetics, including abnormal glucose utilisation and hypometabolism, particularly in white matter [9], may be corrected via utilising ketone bodies as the predominate fuel source The nutritional supplementation and it's neuropsychiatric benefits Acetyl-L-carnitine has been used in some countries as an effective antidepressant agent [10] and in cognitive impairment [11] it has preliminary positive cognitive and behavioural effects, slowing the progression of deterioration. It functions to support the oxidation of fatty acids via enhancing transport of long-chain fatty acids and energy production via facilitating acetyl-CoA, enhances mitochondrial function, modulates neurotransmitter function, increase neurotrophic factors (increased neurogenesis in prefrontal-limbic areas, increased NGF) and as an epigenetic modulator of histone acetylation [12] in the brain. Due to it's role in supporting oxidation of fatty acids and energy production, it was hypothesised to be a useful addition to dietary ketosis. Omega-3 PUFAs [13] have a large body of evidence supporting benefits for brain health, through mechanisms including upregulation of neurotrophic factors, anti-inflammatory activity, membrane modulation and monoaminergic effects. There have been associations of mood and cognitive functioning [14] with serum vitamin D concentrations, with better cognitive performance in the upper range hence it was incorporated as an addition, particularly during winter. 2 Due to the rather restrictive nature of dietary ketosis, a full-spectrum multivitamin including high doses of B-group vitamins and minerals was added Polyphenols also have a range of cognitive benefits, including upregulation of BDNF, anti- inflammatory effects and regulation of oxidative stress, so low carbohydrate options for incorporating them were used. Exercise and it's neuropsychiatric benefits Exercise has a large body of evidence to support it's benefits for mental health and cognitive impairment with higher activity levels associated with better neuropsychological functioning [15]. The benefits are assumed to be linked with increases in neurotrophic factors like BDNF and increases in growth factors, glucagon-like peptide-1, epigenetic factors, increases in synaptic strength (increased neurotransmission, receptor density, dendritic spine formation), cerebral blood flow, immune modulation and brain metabolism which leads to strengthened neural circuitry and connectivity. Antidepressant and anti-stress effects are noted from exercise. Whilst chronic stress increases oxidative stress, neuroinflammation, decreases neurotrophic factors and decreases neurogenesis, decreases learning and memory and increases depression, exercise increases antioxidant enzymes, decreases neuroinflammation, increases neurotrophins (BDNF, IGF-1) and neurogenesis, enhances learning and memory and decreases depression. Exercise is also an important modifiable risk factor for cognitive decline, being able to slow the progression. Cognitive training/remediation and it's neuropsychiatric benefits Cognitive deficits remain particularly resistant to pharmacological interventions in psychotic disorders [16] but there are efforts around tailored interventions targeting cognitive remediation. Similarly, cognitive impairment seems to benefit from enriched cognitive environments. In general, the brain requires cognitive stimulation and assuming the induction of neuroplasticity promoted via diet and exercise, there becomes a window for retraining towards improved cognitive functioning in a variety of neuropsychiatric disorders. Meditation and it's neuropsychiatric benefits Meditation has not only mood [17] stress-reducing and cognitive benefits [18] but often prosocial emotional effects [19]. It is said [20] meditation offers a unique healing opportunity as it offers dimensions of health such as: ⦁ Love and connectedness 3 ⦁ Relief of tension and stress ⦁ Restoring alignment and balance ⦁ Opening to your experience and softening ⦁ Creates a space for all of your emotions ⦁ Improves harmony, joy and well-being ⦁ Freedom from self-clinging and habitual behaviours. One can heal, change, learn and grow more rapidly ⦁ Opportunity to awaken to a spiritual dimension Hypothetical synergy of combining multiple activities It is proposed that the above activities may offer a holistic intervention that synergistically targets a multitude of pathways, from neurobiological to cognitive-emotional, relevant to recovery from a neuropsychiatric disorder including cognitive impairment. Improvements in neuroplasticity offered by diet and exercise may allow more effective learning and memory, thus opening a window for improved cognitive training. After targeting disrupted attentional processing, more tasks can be effectively achieved, which coupled with the meditation aspects, means multiple aspects of psychopathology may effectively targeted. This was explored in a single individual with a complex illness. Coupling these multiple interventions led to a notable gradual improvement in neurocognitive functioning as assessed by online cognitive performance measures of memory and attention. Figure 2. Cognitive scores by time after a short period (several weeks) of intervention, showing a trend towards improved measures of memory and attention 4 Figure 3. A second sample of cognitive performance by time, once again showing general improvements in cognitive performance References: [1] Stephen C. Cunnane, Russell H. 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