Modulation of PFC functions to improve symptoms? The greatest predictor of level of disability in some severe mental illnesses seems to be both negative and cognitive symptom domains but there is often limited options for addressing these domains. Dysregulated prefrontal cognitive dysfunction is associated with multiple neuropsychiatric disorders, "linked to social deficits, affective disturbance, and memory loss in brain 1 disorders, including autism, schizophrenia, depression, and Alzheimer’s disease" [1] The role of ACh and monoamines in PFC functioning is discussed in [2]. There has been pharmacological modulation of basic functions like attention in individuals with neurological and psychological impairments and some efforts towards pro-cognitive strategies in severe mental illness. "The relationship between arousal and cognitive performance follows an inverted-U function whereby optimal attention, learning, and working memory are associated with intermediate levels of arousal" The vigilance model of affective disorders and attention-deficit/hyperactivity disorder links a disturbed arousal regulation to the pathogenesis of psychiatric disorders. Stable arousal regulation provides a simple explanation for the attention deficits Catecholamines: "Release of NE and DA is low during periods of drowsiness, moderate during conditions of alert interest, and high during uncontrollable stress." Optimal levels of NE and DA are essential to proper PFC function. 2 In general, administration of a dopaminergic antagonist declines the efficiency of brain networks similar to the effects of aging [3]. With dopamine, there seems to often be an inverted 'U' shaped response curve to mesocortical dopamine where both low and high levels impair cognition. Dopamine seems to be a more effective regulator of inhibitory control than 5-HT or cholinergic interventions "...low levels of arousal at rest and attentional deficits could stem from a combination of a low-arousal baseline (e.g. low tonic dopaminergic activity) combined with an autoregulatory attempt at compensating for this low baseline (e.g. high phasic dopaminergic activity)" - decreasing arousal through an increase in serotonin levels via SSRIs led to poorer behaviour - NE improves working memory, response inhibition and lessens distractibility through actions at post-synaptic α2A adrenoceptors in the PFC, while DA improves working memory through modest stimulation of D1 receptors in PFC 3 - high levels of NE and DA release, e.g. during stress, impair PFC function through α1, β1, D1 and possibly D4 receptors The noradrenergic system: often been studied in relation to attention and recently in relation to cognitive control. Via β- and alpha-adrenoceptors, NE may act to modulate 'signal-to-noise' levels. α1 and α2 receptors exert unique modulatory actions across distinct cognitive processes [4] "...catecholaminergic activity in the PFC helps to provide stabilization and switching between different representations, for example of rules or objects, that guide behavior" Things like lower-dose α2 adrenergic agonism can have varying effects on cognition depending on dose [5] and in the PFC, at moderate rates of NE release associated with moderate arousal levels, promote working memory. The higher affinity of α2 adrenergic receptors for NE means they are preferentially activated but at higher levels of NE eg stress, lower affinity α1 adrenoceptors become activated which can impair working memory whilst promoting flexible attention [6] Acetylcholine Cholinergic system: focused on modulation of attention- and memory-related brain activity. Attention control requires cholinergic neuromodulation. ACh plays a vital role in the top- down control of attentional orienting and stimulus discrimination ACh: the basal forebrain (BF), has long been associated with different cognitive functions, such as arousal, attention, learning, memory, and even consciousness. -muscarinic and nicotinic receptors contribute to neuronal signatures of attention - nicotinic receptors are also involved in the ability to keep top-down goals in mind (a form of working memory), which may thus affect the strength of attentional control. "Dysregulated phasic cholinergic transients could disrupt attentional abilities of patients suffering from schizophrenia and attention-deficit hyperactivity disorder" "Cholinergic neuromodulation of the prefrontal efferent projections is conceptualized to enhance stimulus processing and to suppress the processing of irrelevant stimuli, distractors, or noise in a top-down fashion" Administration of nicotine and nAChR agonists seems to exert beneficial effects on attention and related cognitive abilities. Changes in nAChRs and mAChRs may regulate the dopamine dysregulation seen in psychotic disorders and in general ACh acts through nicotinic and muscarinic receptors to regulate arousal and cognition [7, 8] Things like CDP-choline seems to activate pre-frontal and frontal areas which have been associated with working memory and sustained attention, also influencing alertness. Particularly combined with caffeine [9], it seems to enhance mental alertness, attention, 4 and working memory and in psychotic spectrum disorders, activated α7-nAChRs where acutely, it improved processing speed, working memory, verbal learning, verbal memory, and executive function in low baseline performers [1] https://www.nature.com/articles/s41380-021-01092-3 [2] https://www.nature.com/articles/s41386-021-01100-8 [3] https://doi.org/10.3389/fnbeh.2012.00053 [4] https://doi.org/10.1016/j.brainres.2015.11.024 [5] https://doi.org/10.1111/j.1460-9568.2011.07815.x [6] https://doi.org/10.1016/j.neubiorev.2023.105306 [7] https://doi.org/10.3389%2Ffpsyt.2022.909961 [8] https://doi.org/10.1196/annals.1417.021 [9] https://doi.org/10.3109/09637486.2014.940286 5