Cancer patients experience symptoms and adverse effects of treatments that may last even after the end of treatments. Exercise is a safe, non-pharmacological and cost-effective therapy that can provide several health benefits in cancer patient and survivors, reducing cancer symptoms and cancer treatment side effects. The purpose of this review is to describe how the physical exercise is capable to reduce cancer symptoms and cancer treatment side effects. We realized a pragmatic classification of symptoms, dividing them into physical, psychological and psycho-physical aspects. For each symptom we discuss causes, therapies, we analyse the effects of physical exercise and we summarize the most effective type of exercise to reduce the symptoms. This review also points out what are the difficulties that patients and survivors face during the practice of physical activity and provides some solutions to overcome these barriers.Related to each specific cancer, it emerges that type, frequency and intensity of physical exercise could be prescribed and supervised as a therapeutic program, like it occurs for the type, dose and duration of a drug treatment. Cancer symptoms and adverse effects of cancer therapies can be resolved or persist for days, weeks, or years. Physical activity is defined as any bodily movement produced by skeletal muscles that results in energy expenditure, which may be unstructured and everyday life activity, exercise that includes prearranged, deliberate and repetitive activity and grassroots sports and competitive sports .The present review explores the impact of physical activity on physical, psycho-physical and psychological aspects on adverse effects of cancer. In particular the physical category includes bone loss and metastases, changes in body composition, cachexia, lymphedema and peripheral neuropathy; the psycho-physical category comprehends pain, fatigue and sleep disorders; the psychological category encompasses depression, anxiety, quality of life and self-esteem. For each aspect we report definition, causes (related to cancer or cancer treatment) and both pharmacologic and non-pharmacologic therapies. At the end of each paragraph we focus on the effect of physical exercise on specific symptoms and we analyse the most effective type of exercise to reduce the symptoms (if reported in the literature). We finally point out what are the barriers between patients/survivors and physical activity and how to overcome these difficulties.Bone loss and diseases can be related to cancer metastasis or to cancer treatments, such as hormonal therapy for breast and prostate cancer patients.Metastatic lesion can cause increased bone resorption , increased bone formation  or both mechanisms (mixed lesions). Bone metastases may cause severe pain, pathologic fractures, compression syndromes of the nerve root or of the spinal cord, metabolic disturbances  and nephrolithiasis . Bones aThe decrease in bone mineral density that characterizes cancer treatment-induced bone loss often brings to osteopenia or osteoporosis, sometimes forcing drug suspension. Osteopenia can be distinguished from osteoporosis by measuring bone mineral density . Cancer Bone loss in cancer patients has to be prevented and bone health has to be maintained by adopting life-style changes such as stop smoking, limit alcohol, supplement calcium intake and vitamin D, as well as take more weight-bearing exercise (see next paragraph). Bone metastasis requires a multidisciplinary management that includes external beam radiotherapy or radioisotopes therapy and bone targeted agents. Bone targeted agents include bisphosphonates  and denosumab. Bisphosphonates accumulate in the skeleton, reduce bone resorption, increase mineralisation by inhibiting osteoclast activity and are used also for widespread bone pain or pain recurrence after radiotherapy. Denosumab is a monoclonal antibody that binds Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL) preventing the binding between RANKL and RANK (Receptor Activator of Nuclear factor Kappa-Β) that lead to osteoclasts activation. Data suggest that the administration of bisphosphonates or denosumab could prevent the formation of breast and prostate cancer bone metastases  and therThere is a consistent body of evidence that exercise has a crucial impact on bone health. The effect of exercise on bone mass is all life-long: exercise prior to the pubertal growth stimulates greater accumulation of peak bone mass, in adults exercise preserves and may stimulate increase in bone mass density and physical activity is capable to reduce bone loss in the elderly . A meta-Impact and weight exercise training has to be preferred for bone health. Impact exercises include physical activities such as running and jumping that causes mechanical loads on bones, stimulating bone formation and promoting structural modifications of the bone tissue. Weight training involves muscle pull and muscular insertion of the skeletal sites of interest producing a delay in the loss of bone mineral density in pre and post-menopausal women with breast cancer .Several studies on physical exercise in cancer patients evidenced a positive effect of impact plus resistance training on bone mass density. High-impact training (such as running and jumping) combined with high-resistance activities are effective in increasing bone mineral density in premenopausal women at the hip and spine level . ExercisCombined training programs of impact and resistance improved bone mass density in the hip and prevented bone mass density loss in the spine in breast cancer survivors with premature treatment-induced menopause , while sA recent trial involving female cancer survivors found that also aerobic training when combined with resistance-training exercise produced a significant increase in bone mass density at the spine, hip and whole body. Aerobic exercise consisted in walking or using the elliptical machines, while resistance-training included upper and lower body resistance exercises provided through use of body weight, dumbbells, elastic bands . PhysicaCancer patients experience muscular and weight changes due to the cancer itself or to the cancer treatments, such as loss of muscular mass, increased fat mass and weight gain. Increased fat mass and obesity are significantly associated with increased cardio-metabolic disease risk that lead to an augmented mortality of cancer survivors, while reduction in muscular mass could promote the development of cancer syndromes such as cachexia, making important to assess their presence and to prevent worsening due to these changes.Muscular changes in cancer patients include significant impairments in muscle strength and loss of muscle mass, related to both cancer itself and cancer treatments.Causes of reduced muscle mass induced by cancer include malnutrition, physical inactivity, altered metabolism and increased proinflammatory cytokines such as Tumor Necrosis Factor- α (TNF-α), Interleukin-1-β (IL1-β) and Interferon-γ (IFN-γ), that seem to upregolate muscle degradation as detected in muscular biopsies of cancer patient.Cancer therapies may affect muscle mass with different mechanisms: chemotherapy has a cytotoxic and an anti-proliferative effect, but also cause nausea, diarrhea and anorexia, which worsen the nutritional intake, while surgery and/or radiotherapy may destroy muscle structures in the treated areas . Loss ofLoss of muscle mass may be masked by the increase in fat mass and the weight gain associated with the cancer therapy such as chemotherapy, steroid medication and hormonal therapy. Increase in fat mass is a typical side effect of androgen deprivation therapy in prostate cancer patients. The increase in fat mass usually induced by the androgen deprivation therapy predispose prostate cancer patients to develop cardiovascular diseases and it’s also associated with cancer recurrence and higher specific prostate cancer mortality . CisplatWeight gain can be caused by chemotherapy, steroid medication and hormonal therapy. Weight gain is common in breast cancer patient receiving chemotherapy and survivors given that incidence is ranging from 50% to 96%, with 20% of them increasing more than 10 kg . Weight Weight gain and increase of fat mass can be controlled by following a diet  and by exercise (see next paragraph). The reduction of muscle mass may bring to cancer cachexia, so it’s important to recognize its loss and start as soon as possible preventing the development of precachexia and cachexia .Exercise is one of the main treatment that can act on muscle strength, fat mass and therefore weight gain.Either resistance or strength training cause an increased synthesis of actin and myosin, resulting in reduced muscle weakness, augmented muscle mass and thus muscle strength . In breaSimilarly, in breast cancer patients undergoing chemotherapy, a single aerobic exercise, such as a walking training program , caused a significant weight and body fat percent reduction . In prosSeveral studies found positive results of physical exercise in prostate cancer patient that received androgen deprivation therapy, suggesting that exercise should become an important part of clinical care in these patients. In particular, 12-month of impact plus resistance exercise program can increase maximal leg strength .Physical exercise is not only capable of reducing fat mass, but also of lowering the consequences of fat mass increase, such as greater risk of cardiac and metabolic disease. In particular, exercise causes cardiorespiratory changes (such as lowering blood pressure) and metabolic changes  that can prevent cardio-metabolic cancer comorbidities .Cancer cachexia is a paraneoplastic syndrome characterised by a progressive loss of skeletal muscle mass (with or without loss of fat mass) that cannot be completely reversed by conventional nutritional support and leads to progressive functional impairment. Approximately 20% of cancer deaths are directly caused by cachexia .2; females <5,45 kg/m2) concomitant with any degree of weight loss >2% . To. To59]. Several studies conducted in Walker 256 tumour-bearing rats  reported that aerobic exercise is associated with a retarded skeletal muscle degradation and a reduction of body mass loss .Given the possible effects of both resistance and aerobic exercises, a combination of these trainings has been recently proposed to treat cachexia. However, definitive regimens have to be further developed to support the efficacy and safety of exercise training for cancer cachexia patients .Peripheral neuropathy is a condition that results from peripheral nerves damage. Peripheral neuropathy can occur as a paraneoplastic manifestation, but in most of the cases it is a side effect of anti-cancer treatment, and therefore is called chemotherapy-induced peripheral neuropathy (CIPN).The supposed pathogenesis of CIPN is due to the neurotoxic effects of chemotherapy and the lack of protection of the peripheral nervous system. The cell bodies of the dorsal root ganglia are particularly vulnerable to neurotoxic damage because the blood–brain barrier doesn’t protect them; furthermore they are supplied by fenestrated capillaries that make them more accessible to neurotoxic circulating agents. The neurotoxic effects of chemotherapy are probably related to the drug mechanisms of cytotoxicity in cancer cells, so the neurotoxicity depends on either the agent used and the cumulative dose .Peripheral neuropathy consists commonly in a pure sensory neuropathy, with sensory symptoms , but sometimes it can cause motor or autonomic symptoms . Patients suffering from CIPN usually experience firstly numbness and loss of deep tendon ankle reflexes and then paresthesia and loss of positional sense .CIPN prevalence is estimated to be about 68% in the first month after chemotherapy, 60% at 3 months and at 6 months 30% of patients continue suffering from CIPN  determinCIPN influences the course of disease and treatment: sometimes it’s necessary to lower the chemotherapy dose, delay or even stop the cancer treatment . CIPN seChemotherapeutics that causes CIPN include platinum drugs , Microtubule-Targeting Agents , proteasome inhibitors (such as bortezomib) and angiogenesis inhibitors  .Platinum chemotherapies, commonly used for the treatment of solid tumours , determine a sensory peripheral neuropathy  and often cause worsening for several months after the end of treatments, a phenomenon called “coasting” Table  72]. Pl. Pl72]. Taxanes (such as paclitaxel and docetaxel) cause a sensory neuropathy that typically includes paresthesia, numbness or neuropathic pain in hands and/or feet. Symptoms often improve within 3-6 month after the end of the treatment, but sometimes the neuropathy doesn’t resolve .Vinca alkaloids  alter the axonal cytoskeleton (length and orientation of microtubules) inducing a sensory neuropathy similar to taxanes but are also associated with an autonomic neuropathy .Although the neurotoxicity mechanisms of thalidomide are unknown, CIPN is one of the most common side effects of this drug, a glutamic acid derivative used for the treatment of the multiple myeloma, and symptoms are often both sensorial and autonomic .Bortezomib is a proteasome inhibitor used for multiple myeloma that causes chronic sharp sensation, burning pain, and sometimes autonomic neuropathy. The neurotoxic action of bortezomib is probably due to tubulin polymerization, mitochondrial changes, oxidative stress and increased production of glutamate .Bevacizumab  when administered in combination with oxaliplatin, can enhance peripheral neuropathy induced by the platinum agents .Many agents have been tested for the CIPN prevention, such as acetyl-L-carnitine, amifostine, amitriptyline, glutathione, nimodipine and vitamin E, with different results. Anyway, the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines don’t recommend any agents for the prevention of CIPN in cancer patients undergoing neurotoxic agents, because there aren’t high-quality evidences for benefits derived from these agents .ASCO recommend duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant with positive results for the treatment of CIPN . TopicalA multifunctional approach for the treatment of CIPN includes also nonpharmacologic interventions, such as acupuncture , scramblDespite the widespread belief that physical activity is not safe for persons with peripheral neuropathy because of the augmented risk of falling, Kruse et al. reported that exercise is feasible and safe for diabetic patients  with peripheral neuropathy .Also cancer patients and survivors suffering from CIPN are at risk of postural instability, falls and fall related injury, but data suggest that exercise is a safe intervention for these patients .Exercise has a positive role on peripheral neuropathy in mouse receiving paclitaxel. A study that examined the effect of a rigorous treadmill exercise program, started 1 week before administration of the drug and continued during the therapy, found that exercise could partially reduce axonal degeneration. In particular they found that mouse which exercised did not show a reduction in epidermal nerve fiber density, did not suffer from thermal hypoalgesia and did not have an elevated detyrosinated tubulin levels, features typically associated with paclitaxel administration .Also clinical trial conducted on patients investigated the role of exercise in the management of peripheral neuropathy . Two stuHow exercise may work on nerves? This question has only a partial answer, because the mechanism is complex and is not clear. Exercise contrasts the progressive muscle mass atrophy associated with neuropathy by increasing muscular strength. Exercise is also associated with improved muscle reinnervation and increased axon regeneration . ProbablIn patients with peripheral neuropathy, some studies tried to define the most effective type of training, examining strength and balance training. Balance training has the aim to improve stability and prevent falls by strengthen legs and core muscles. Balance exercises include stance on heel/toes, tandem stance, one leg stance and different kinds of walking. Allet et al. reported that a strength and balance training program  is able to increase walking speed, improve balance and strength and reduce fear of falling in patients with peripheral neuropathy . A systeIn summary, exercise  is a potentially effective preventive and therapeutic approach to contrast and reduce the neurotoxic effects of chemotherapy  and positively impacts the lives of patient with CIPN. The mechanisms is not completely clear but probably involves BDNF and GDNF, that promote muscle reinnervation and axon regeneration.Lymphedema is an abnormal collection of protein-rich interstitial fluid (lymphatic fluid) that results from lymphatic insufficiency and inadequate lymph transport. Lymphedema is usually classified as primary or secondary. The primary lymphedema has a congenital origin . The secondary lymphedema has an infective or iatrogenic origin, which can be surgical  or related to radiation therapy because of the lymph nodes fibrosis. Lymphedema can cause complications such as delayed wound healing, skin break-down, infections, lymphangitis and lymphangiosarcoma, a rare form of lymphatic cancer. Lymphedema can also influence daily activities by causing a restriction in range of motion, pain, increased skin tension and a sense of heaviness of the affected limb. Impairment of function reduces the ability to work and decreases quality of life .The overall risk of lymphedema for all cancers is estimated to be 15.5% . The risUpper extremities lymphedema is a long-term complication of axillary lymph node dissection or even of sentinel lymph node biopsy alone. The degree of lymphedema depends on the number of lymph nodes removed and the extent of radiation treatment to the axillary region. Most of breast cancer survivors develop lymphedema within three years from the treatment .Lower Limb Lymphedema is the most frequent expression of lower body lymphedema and is generally observed in patients treated for gynaecologic malignancy or prostate cancer. Incidence and timing of secondary lower body lymphedema is variable depending on the study because there isn’t a uniform diagnostic definition .The management of lymphedema consists in surgical or non-surgical (conservative) therapy. The conservative treatment is referred to complex decongestive therapy, which includes manual lymphatic drainage, compression therapy and exercise (see below).Manual lymphatic drainage consist in slow, very light repetitive circular massages done in a specific sequence to facilitate the removal of retained interstitial proteins, redirect fluid to lymphatic vessels, stimulate lymph flow and promote the development of accessory lymph pathways .Manual lymphatic drainage is used in combination with compression therapy, which consists in setting low-stretch multi-layered bandages to improve fluid reabsorption and enhance lymphatic contraction and flow .The surgical therapy is a secondary option indicated in case of fail or strict adherence to complex decongestive therapy . MedicatPhysical exercise can be both a treatment and a prevention strategy for lymphedema.2 is a significant risk factor for lymphedema, so physical activity is important to prevent this condition  cle cle99] cA recent systematic review of six articles (involving 805 breast cancer survivors) assessed the efficacy of resistance exercise among patient with or at risk for lymphedema . This reThe patient has to follow the prescription of the load’s weight, the technique and the number of repetitions indicated by the exercise specialist. In particular, at the beginning of the program, survivors should receive specific instructions by the fitness trainer, then they should be encouraged to exercise on their own. This kind of training can be safely performed two to three times a week of non-consecutive days .The necessity of wearing compression garments during exercise is still uncertain: NLN recommends it especially for breast cancer survivors who have lymphedema, while Nelson, in his review, focused on a trial not requiring garments and pointed up that no changes to lymphedema status were reported among participants not wearing the compression garments , 102. SuCancer pain is a common symptom that negatively affects quality of life and significantly impacts on daily activities of cancer patients. It can be directly caused by cancer (due to compression of surrounding structures by the cancer mass or invasion of bone by metastatic tissue), related to the cancer consequences (such as bed sores due to stay in bed), induced by cancer treatments or caused/aggravated by comorbidities of the patient .Cancer pain can be classified in acute, chronic (if it lasts more than 3 months) and breakthrough pain, that is an acute exacerbation of pain on the background of a well-controlled, persistent, stable cancer pain . Cancer There are several scales to assess pain intensity such as the verbal rating scale , the numerical rating scale  and the visual analogue scale  .It is estimated that about 25% of cancer patients suffer from pain at cancer diagnosis, about 33% during treatment and approximately 75% during advanced stages , while tThe localization of cancer strongly influences the prevalence of cancer pain, that is the highest (70%) in patients suffering from head and neck cancer, whereas ranges from 50 to 60% in patients affected by gynaecological, gastrointestinal, lung, breast and urogenital cancer Table  108]..108].Both surgery, chemotherapy and radiation therapy can cause cancer pain. Surgery usually causes acute pain, but sometimes the patient suffers from phantom pain  or develops a chronic post-surgical pain syndrome. Chemotherapy can determine pain arising from the infusion site  but also from mucositis, painful ulceration or peripheral neuropathy. Radiotherapy may cause osteonecrosis or chronic post-radiotherapy pain syndrome .Cancer pain is underreported and undertreated and it’s estimated that more than 40% of patients under therapy receive insufficient treatment .The pharmacologic treatment for cancer pain comprehends opioid and non-opioid analgesics and also adjuvants.Non-opioid analgesics include paracetamol  and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, which inhibit cyclooxygenase (COX) an enzyme that converses arachidonic acid to prostaglandins, mediators of inflammation. The main side effects of NSAIDs are gastrointestinal and renal impairments .Opioid analgesics interact with opioid receptors and are divided in weak  and strong opioids . Common side effects of opioid treatment are sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance and respiratory depression . To enhaThe European Society for Medical Oncology (ESMO) guidelines recommends oral analgesic drug as the first line therapy for cancer pain according to the severity of the symptom: in particular paracetamol and/or NSAIDs are recommended for treating mild pain (defined as <3 on NRS); association of weak opioids and non-opioid analgesics for the treatment of mild to moderate pain (defined as 3-6 on NRS); strong opioids in combination with non-opioids analgesics for moderate–severe cancer-related pain (defined as >6 on NRS) .An alternative pharmacological strategy for the management of mild to moderate pain is to administer low dose of strong opioids instead of the association between weak opioids and non-opioid analgesics .Additional medications called adjuvants can be used to increase the effect of primary analgesic or to manage particular situations such as neuropathic pain and cancer related bone pain. Antidepressants  and anticonvulsants  are used to treat neuropathic pain, while bisphosphonates plays an important role in the management of cancer related bone pain .A multidisciplinary approach to cancer pain includes psychosocial interventions , which are able to impact on pain intensity and on and pain interference . HoweverCancer pain produces an important economic burden. Direct pain-related costs are related to analgesic medication and hospitalization for uncontrolled cancer pain. Cancer pain causes also indirect costs due to loss of productivity  and psychosocial costs (pain forces undesirable changes in lifestyle such as isolation) . Also foDespite the widespread conviction that patients suffering from cancer pain have to avoid physical exercise, a study on breast cancer patients suffering from muscle and joint pain during adjuvant chemotherapy found that patient pain perception was not worsened by training . In suppPhysical activity is a sustainable therapeutic alternative for chronic  and acutThe mechanisms by which physical exercise may work on pain are not completely known. Exercise is able to induce hypoalgesia , a relief from acute pain that characterizes the period after the activity and that may result from an endogenous pain inhibitory mechanism called conditioned pain modulation (CPM)  in whichThe EIH has been extensively studied in healthy individuals: results show that EIH is associated with higher-intensity and longer duration activities, but recently EIH has also been related to shorter bouts of moderate intensity . Both acDifferent mechanisms have been described for the modulation of cancer pain by physical activity: it is able to reduce chronic muscle pain by lowering the phosphorylation, increased in chronic muscular pain, of a subunit (in particular NR1) of the N-methyl-D-aspartate receptor  in the central nervous system .ATP pathway at both spinal, supraspinal and peripheral levels in mouse model . A. A132]. Evidence suggests positive effects of exercise in most of neoplastic patients suffering from cancer pain and they can take advantage of exercise approach. Nevertheless, the type of exercise indicated for each type of cancer pain has to be personalized.The National Comprehensive Cancer Network  defines Cancer-related fatigue (CRF) as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive exhaustion related to cancer or cancer treatment that is not proportional to recent efforts and interferes with daily activities . The tirThe pathophysiology of fatigue is multifactorial and the specific mechanisms involved in it are unknown. Causes of fatigue may be referred to metabolic imbalance, immune system disorders and increased cytokines such as NF-κB and TNF-α Table  137]. T. T137]. Any kind of cancer can cause CRF, but fatigue occurs more often with malignant solid tumours such as pancreatic and breast cancer, and hematologic disease as lymphoma . FatigueFatigue in patients with cancer has been under-reported and under-treated. The patient doesn’t declare this symptom because usually thinks that nothing can be done to improve his/her condition. This is why fatigue should be screened, classified and the physician has to inform the patient about fatigue and its natural history. This education should be offered to all patients with cancer, especially to those who are at the beginning of fatigue-inducing treatments .Many interventions have been evaluated to prevent or treat CRF. The treatment of CRF can be pharmacologic or non-pharmacologic. Pharmacologic interventions include stimulants , antidepressants   and sterNon-pharmacologic interventions include: psychosocial interventions such as support groups , comprehPhysical activity is one of the non-pharmacologic interventions that have the strongest evidence for treating fatigue. A large meta-analysis of 70 studies, 27 of which included patients after treatment, reported that exercise significantly reduces CRF by 32% or 38% during or after cancer treatment respectively .A very recent meta-analysis of 113 randomized clinical trials (11525 patients) compared the mean weighted effect sizes (WESs) of pharmaceutical treatment, psychological strategy, exercise and exercise plus psychological interventions on fatigue. The authors found that exercise has the greatest impact in reducing fatigue when compared to other therapies . AccordiThe mechanisms through which exercise reduces fatigue have not been fully elucidated. It has been suggested that physical activity could reduce CRF by improving functional capacity, resulting in a reduced effort to sustain daily activities and improvement in the capacity to recognize a reduced body weakness and exhaustion . ResistaASCO recommends to patients 150 minutes per week of moderate aerobic exercise with an additional two to three sessions of strength training, such as weight lifting, unless contraindicated . The exePrevious guidelines suggested that exercise prescriptions depend on the level of fatigue. In fact, asking patients to rank fatigue on a numeric rating scale from 0 to 10, CRF can be classified in mild (1-3), moderate (4-6) and severe (7-10). Patients with mild fatigue had to perform progressive aerobic exercise program that includes 20–30 min per session, 3 to 5 days per week, at 60%–80% of maximum heart rate and resistance exercises that included 8–10 exercises for major muscle groups of upper and lower extremities and trunk, 2 to 3 days per week. Patient with moderate fatigue were encouraged to increase exercise through repeated bouts of 5–10 min per session; the resistance exercise program was similar to the aforementioned one for patients with mild fatigue, but for patient with moderate fatigue it was proposed to increase exercise frequency or duration before increasing intensity. Patients with severe fatigue were encouraged to try frequent sessions of low-intensity exercise  spaced throughout the day , difficulty with sleep maintenance  and significant impairment in daytime function . The preSleep disturbances can be perpetuated and insomnia often becomes chronic, persisting for at least one month and causing several form of daytime impairment . ChronicThe pathophysiology of sleep disorders is not clear but many predisposing factors can determine insomnia among cancer patients since they suffer from anxiety and depression  and since they are exposed to cancer treatments and supportive care, which may contribute to sleep disturbances . Older aCancer treatments may influence insomnia: the prevalence of sleep disturbances in cancer patients who undergo surgery, radiation therapy or chemotherapy is 49%, 39% and 35% respectively .Lung (34%), breast (48%) and gynaecological (30%) cancer patients have an higher sleep problem incidence and experience sleep disturbance. Hypnotics and sleep medication are used by 40% of lung cancer patient and by 28% of breast cancer patients. Prostate cancer patients suffer from sleep maintenance due to frequent voiding. Gastrointestinal patients show the lowest prevalence of sleep disorders (7%) Table  160]..160].Treatment of sleep disturbances is multimodal and includes both pharmacologic and non-pharmacologic approaches. Pharmacologic strategies include hypnotics (both benzodiazepine and non-benzodiazepine such as zopiclone and zolpidem), antidepressants, antihistamines and melatonin. The first line pharmacotherapy approach is the combination of short-acting benzodiazepines with non-benzodiazepines hypnotics for less than 4 weeks, but in most cases is necessary to continue therapy for long periods , even ifNon-pharmacologic therapies comprehend relaxation therapy, sleep education, stimulus control, sleep restriction and cognitive behavioural therapy. Relaxation therapy reduces somatic and muscular tension by first slowly tensing and then relaxing each muscle group and is associated to meditation to lower thought and preoccupations. Sleep education is used to remove environmental disturbing factors and discourage behaviours that may interfere with sleep. Stimulus control is important to consolidate the association of the bed/bedroom with sleep (for example it is recommended to not watch TV or read in bed) and to reinforce the sleep-wake cycle (going to bed at the same time every night and waking up at the same time every day). Sleep restriction therapy consists in reducing the time for sleeping, to improve sleep quality . CognitiExercise has many effects on sleep duration, architecture and quality.Exercise directly influences the circadian system, resulting in an increased total sleep time as well as time in deep sleep (slow-wave sleep), which improves sleep quality. In fact, deep stages of non-rapid eye movements (REM) sleep induce neurophysiological restoration and a physiological muscle and tissue recovery. In addition, exercise reduces sleep-onset latency  and REM sleep .The direct effect of decreased REM sleep on sleep quality remains unclear, but it is suggested that REM sleep reduction has an antidepressant effect, so exercise acts also indirectly by reducing depression, a predisposing factor of sleep disturbances .Exercise also influences thermogenic regulation, causing temperature elevation. The increase in core temperature seems to promote the initiation of sleep by activating heat dissipation mechanisms controlled by the hypothalamus. In addition, people affected by insomnia have an impaired nocturnal temperature down-regulation and the thermogenic effects of exercise may regulate this mechanism .Furthermore, exercise may modulate sleep-mediating cytokines, such as IL-6 and TNF-α. In particular, exercise promotes the release of IL-6 in direct proportion to exercise intensity, muscle mass involved during exercise, duration and training status. The peculiarity of exercise-induced release of IL-6 is that the release is immediate but transient. This time course of IL-6 has also an anti-inflammatory action: promotes the release of soluble TNF-α receptor (sTNF-R) and inhibits the production of TNF-α. IL-6 and TNF-α are elevated in cancer patients and are able to activate the hypothalamic-pituitary-adrenal (HPA) axis resulting in short sleep duration and sleep disturbances .The USA National Sleep Foundation considers exercise as a non-pharmacological intervention to improve sleep quality. Many studies focused on the exercise approach to treat sleep disturbances showed significant improvements in objective (Polysomnography) and subjective  measurements of sleep quality among patients with chronic primary insomnia . These bWhen exercise should be performed to improve sleep quality? Morning exercisers get the most favourable sleep outcomes. However, despite the belief that exercise should not be performed in the evening because it may reduce sleep duration and quality, data reports that individuals who performed vigorous evening exercise obtained an equal or higher sleep quality compared to the days without exercise . Sleep aSeveral randomized control trials also explored the possible benefit of exercise as a therapy for sleep disturbance in cancer patients, with different results , 176. CoWhich kind of physical exercise could reduce sleep disorders? Long-term moderate aerobic exercise  showed significant improvements in sleep in individuals with chronic primary insomnia . Most inAlso relaxation exercises are able to improve sleep quality by reducing muscle tension and promoting muscle relaxation . In partAccording to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5), the diagnosis of anxiety requires excessive anxiety or worries that are difficult to control and impair function, along with at least 3 of the following symptoms lasting most of the time over the past 6 months: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty in concentrating, irritability, muscle tension and sleep disruptions. A major depression diagnosis requires at least 5 of the following symptoms most of the time in the past 2 weeks: sadness , loss of interest or pleasure in most activities, significant changes in weight or appetite, sleep disruptions (including sleeping too much or too little), psychomotor slowing or agitation that is observable by others, fatigue or loss of energy, feelings of guilt or worthlessness or feeling like a burden, difficulty concentrating or indecisiveness and thoughts of being better off dead or active suicidal thoughts or plans .Depression and anxiety are two common symptoms in cancer patients and survivors. The prevalence of depression in cancer patients ranges from 8% to 24% depending on the type of instrument used to assess the diagnosis of depression (either diagnostic interviews or self-report instruments), type of cancer and treatment phase . IncidenCancer patients might suffer from depression and anxiety for many reasons: in response to cancer diagnosis, to the symptoms associated with cancer and to side effects of cancer therapies (such as pain and fatigue) and because of fear of disease recurrence or progression . In factDepression in patients with cancer may cause increased hospital stays, physical distress, lower treatment adherence, reduced quality of life  and incrCurrent treatments for depression in cancer patients and survivors include pharmacological interventions and psychotherapy, even if a high number of cancer patients with depression do not receive a proper antidepressant treatment . PharmacIn cancer patients there are low quality evidences about the effectiveness of antidepressants for the prevention and treatment of depressive symptoms . In addiPharmacologic treatment for anxiety in cancer patients includes antidepressants (such as imipramine and mirtazapine) and benzodiazepines  .Psychosocial interventions can reduce depressive and anxiety symptoms in patients with cancer. Some of the most common interventions are: cognitive behavioural therapy, supportive-expressive group therapy , problem solving therapy  and mindfulness exercises (a relaxation training to reduce stress and concerns) , 196.Exercise is a prevention strategy that reduces the onset of clinical depression and anxiety . PhysicaThe neurophysiologic mechanisms potentially responsible of these anxiolytic and antidepressant effects are not known, but several hypotheses have been formulated.Depression is associated with structural changes of central nervous system, such as a reduction of volume of the hippocampus, detected by imaging studies . Brain nThe hypothalamo-pituitary adrenal axis is influenced by physical exercise exerting the ability to improve mood  .Physical activity is capable to lower anxiety sensitivity (a characteristic inclination to think that anxiety itself will lead to catastrophic consequences) . In addiExercise has also long-lasting effects (that are produced when exercise becomes part of the routine) such as improvements in global self-esteem as well as in physical self-concept .The guidelines of the American Psychiatric Association (APA) recognize that exercise has a role in the treatment of depression by improving mood and consider exercise as a non-pharmacological intervention – alone or in addition to pharmacologic treatment – to manage depression. A meta-analysis of 49 trials that compared exercise with no treatments or alternative treatments for anxiety found that the exercise group showed statistically significant anxiety reductions when compared to control and to alternative treatment groups (except for pharmacotherapy) . A studyAnother study that focused on the comparison between physical exercise (running on a treadmill for 30 minutes 3 times a week for 16 weeks) and sertraline found that at month ten of follow up the exercise group showed a significant reduction of depression when compared with the sertraline group. These data suggest that exercise may have a more lasting effect than medication .Many randomized controlled trials found a positive impact of exercise on depression and anxiety symptoms, both on lung, colon and breast cancer patients –213. TheSeveral studies and metanalisis concerning both cancer patients and survivors tried to find which type and dose of exercise can improve the symptoms of depression or anxiety. A meta-analysis done by Brown et al.  that incA study conducted on lung cancer patients proposed a home-based walking exercise  and found that this kind of training can reduce anxiety and depression .In summary, positive effect of exercise on anxiety and depression is well evidenced and exercise is a potentially powerful treatment of depression and anxiety.Quality of life is a broad multidimensional concept referred to subjective evaluations of physical, emotional and social dimensions, as well as stress level, sexual function and self-perceived health status. Health-related quality of life (HRQOL) focuses on the influence that physical and mental health status directly causes on quality of life. HRQOL is usually measured through multiple questions regarding self-perceived health conditions and physical and emotional functioning .The cancer diagnosis and its treatment change forever patient’s life and affect his/her quality of life, according to physical symptoms and psychological aspects such as the perception of decreased life expectancy. As the number of cancer survivors continues to increase, there is an increasing focus on long-term management of quality of life in these patients.Global self esteem is generally defined as the individual’s evaluation of his/her own worth, but is also conceptualized as the sum of domain-specific self-concepts  . PhysicaObesity and inactivity are related with poorer quality of life among cancer survivors , 225, whSeveral trial and reviews concerning different kind of cancer focused on the positive impact of exercise on quality of life. Koutoukidis et al. found that physical activity improved quality of life of endometrial cancer survivors . In headA systematic review concluded that exercise positively influenced quality of life in breast cancer patients  and PhilThese results are confirmed by a Cochrane review that included 40 trials (with 3694 participants) and evaluated the effectiveness of exercise on HRQOL in cancer survivors. Participants were diagnosed for breast, colorectal, head and neck, lymphoma and other cancers. The exercise intervention could be variable and included strength training, resistance training, walking, cycling, yoga, Qigong, or Tai Chi. The results suggested that exercise compared with control has a positive influence on physical, psychological and social aspect of HRQOL. Evidence indicates that since exercise increases physical functioning, reduces fatigue syndrome and sleep disturbances is capable to improve quality of life. Exercise influences psychological well being by lowering the person’s worries about his/her cancer and improving the body image/self-esteem. Exercise also helps the way the person deals with emotions and sexuality and has a positive impact on social well-being.However, physicians do not recommend exercise with adequate incentive, push and motivation, even if it has been found that patients who received oncologists’ exercise recommendation and motivation significantly increased moderate intensity exercise and exercise frequency Table  232]..232].Quality of life depends on various aspects and different types of exercises may have an influence on different aspects of quality of life. An interesting example of non-conventional physical activity in survivors was investigated by a Danish study that tested a community-based recreational football as a novel strategy to promote physical activity in prostate cancer survivors, with positive results .A systematic review concerning breast cancer survivors indicated that a combination of both aerobic exercise and strength training could provide the most benefit for the quality of life . More daPhysical exercise  is an effective strategy to improve physical self-concept and global self-esteem. Exercise acts on physical self-concept by increasing the level of endurance, the capacity to learn sport skills and maintain physical fitness. Physical activity also improves the perceived attractiveness of the body and self-confidence in appearance, as well as the perceived physical strength  . ExercisThere is consistent evidence that physical activity is associated with improvement in self esteem in breast cancer survivors . A recenPhysical self-esteem consists of three subdomains: physical condition, attractive body and physical strength. Resistance exercise training seems to be the most effective type of training to improve self-esteem in breast cancer survivors because it acts on all the three subdomains of physical self-esteem, while aerobic training apparently improved mostly the attractive body domain. The combination of the two programmes (resistance and aerobic) is not more effective than the single-modality programs Table  237]. I. I237]. Cancer survivors are not easy to convince in participating physical activities programs, in fact they often reports barriers to physical exercise. Barriers can be classified in disease-specific limitations, such as illness, pain, fatigue; socio-economic barriers such as financial difficulties, lack of time, transportation issues, child care problems  and indiTo overcome these barriers survivors should be encouraged by counselling and motivational interviewing with physicians, physical therapists and trainers. At the beginning of the program patients should explain their expectations and attitudes toward physical exercise. Then survivors should receive an education on exercise training principles from physical therapists and trainer and at least the first sessions should be supervised to ensure correct exercise performance. The role of the physical trainer appears fundamental in increasing exercise adherence of cancer patients and survivors to the program. Therefore in each program there is the need of educated practitioners to work in team with physicians and physical therapists.Survivors should be encouraged to monitor both the physical activity  and the daily activities outside the exercise setting and to report the perception of symptoms before, during, and after exercise. This progressive education of the patient provided by the physical therapists and trainer may be the key to keep the patient’s adherence to exercise program. It’s important to encourage social contact during exercise: exercise with a partner or in a group setting .Ideally, exercise should begin at the time of diagnosis, to reduce the cancer symptoms and the progressive side effects of the treatments. If physical activity is offered at the beginning of the disease, patient probably has the physical capacity to undertake and complete programmes, and will get satisfaction from physical activity, will get used to it and will maintain an active physical activity during and after cancer treatments .Only about 50% of patients complete the exercise programme . PatientMotivation may increase as the physical training goes on. A recent study proposed to rectal cancer patients to attend supervised aerobic exercise sessions during and at the end of neoadjuvant chemo-radiotherapy treatments. Patients were provided with the option of continuing with the supervised exercise program, completing an unsupervised exercise program, or a combination. The study compared perceived benefits, harms, enjoyment, support, difficulties and barriers for exercise both during and after neoadjuvant chemo-radiotherapy treatment. There were statistically significant improvements in perceived enjoyment, difficulties and support during the supervised exercise program: this positive motivational response influenced exercise adherence. In fact, after the end of neoadjuvant chemo-radiotherapy treatments, patients reported being quite motivated to start with the unsupervised exercise program until the surgical treatment. Surprisingly, even if the exercise was not supervised, patients reported an increased perceived social support. The majority of patients also reported that the exercise program post neoadjuvant treatment helped them to prepare for surgery .A study conducted on lung cancer survivors found that a 10-week supervised progressive resistance training program may improve some motivational outcomes on the basis of the theory of planned behaviour . In particular there was a significant increase in self-efficacy (the ease of performing a behaviour) and the perceived controllability  .The HELP  trial reported that a 12-week one-to-one supervised aerobic exercise program in lymphoma patients receiving chemotherapy had positive effects on motivation, resulting in significant improvements in exercise behaviour at 6-month follow-up .In summary, patients’ adherence to exercise increases as patient keep moving, although initially his/her motivation may be poor and is more strict if a supervision runs along the program.The possibility to perform physical activity depends on environmental factors such as social support and positive social relationships that make easier to exercise. In fact, receiving support from family and friends as well as from the community predicts engagement in healthy behaviour such as physical activity , 246. InSeveral studies assessed cancer patients express preferences by submitting them questionnaires. In these studies the majority of patients showed preferences for walking and strengthening exercises, chose the morning activities and moderate intensity exercises. Patients also reported that the better time to start physical activity was before starting treatment or 3–6 months post-treatment. Motivational strategies such as exercise being fun, incorporating music and variety, establishing goal setting were appreciated by the patients and would facilitate them to exercise , 249. AnThe evidences that we reported show that physical exercise provides benefits on several symptoms of cancer and side effects derived from cancer treatments regarding physical, psychophysical and psychological aspects. Thus, exercise in cancer patients and survivors should be proposed and started as soon as possible to enhance motivation. A multidisciplinary offer of training, frequency and setting of physical activity as well as the caregiver’s support are important to increase exercise adherence. Finally, the most effective type of exercise, optimal exercise frequency and intensity based on the type of cancer should be prescribed and supervised as a therapeutic program like it happens for the type, dose and duration of a drug treatment.


The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside ‘metastasis-directed therapy’ to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years. Prostate cancer is the commonest cancer and the most frequent cause of cancer death in Western men . The medThe standard treatment options and guidelines for prostate cancer (PCa) patients diagnosed with metastatic progression following primary treatment have remained largely unchanged over the last decade ••. AndroDecreasing primary tumour burden, through cytoreductive or radical surgery, radiotherapy or both together has been shown to improve survival in a number of metastatic malignancies. Cytoreductive surgery has shown survival benefit in colon , breast There are currently no reported prospective data regarding a survival benefit for patients with metastatic prostate cancer who subsequently undergo treatment of the primary tumour. However, a number of retrospective studies support this strategy. A sub-group analysis of the SWOG 8894 trial found that 1286 men with metastatic prostate cancer showed a reduced risk of death for those who had previously undergone radical prostatectomy compared to those that had not . Recent Metastasis-directed therapy (MDT) is usually reserved for a sub-set of patients with a limited number of metastases  and therefore represents those patients defined as oligometastatic. The aim is to control the cancer and slow down any further metastasis while avoiding or delaying the toxicity associated with the use of systemic therapies . This isIn order for clinicians to safely and ethically offer patients surgery and/or radiotherapy for oligometastatic prostate cancer, it is important to collect high quality evidence, ideally from randomised controlled trials. The Surveillance or metastasis-directed Therapy for OligoMetastatic Prostate cancer recurrence (STOMP) trial is a phase II RCT being run from Belgium that will report in 2017 . In patiClearly, in the next few years, the evidence supporting how to best treat oligometastatic disease will be strongly progressed and allow clinicians to better advise their patients. Of note, the new imaging technology, for example, PSMA-targeted PET agents, that are being rapidly adopted in some parts of the world is likely to change the clinical workflow in terms of the way patients are staged. We await with interest how these more accurate imaging strategies will impact on the numbers of patients being diagnosed with oligometastatic disease, and how it changes treatment practices.


The trillions of microbes living in the gut—the gut microbiota—play an important role in human biology and disease. While much has been done to explore its diversity, a full understanding of our microbiomes demands an evolutionary perspective. In this review, we compare microbiomes from human populations, placing them in the context of microbes from humanity’s near and distant animal relatives. We discuss potential mechanisms to generate host-specific microbiome configurations and the consequences of disrupting those configurations. Finally, we propose that this broader phylogenetic perspective is useful for understanding the mechanisms underlying human–microbiome interactions. A decade ago, very little was known of the inventory of microbes that inhabit different parts of the human body, how they assemble into communities of varying levels of complexity, and how they relate to microbiomes in other species. Recent improvements in technology for collecting and analyzing DNA sequence data make these questions accessible for the first time. Various aspects of the microbiome have been correlated to a surprising number of human diseases [Clostridium difficile infection [We are in the midst of a revolution in our understanding of the human iome Box . A decadnfection . More brnfection . Given tIn this review, we focus on the gut microbiome, as surprisingly little comparative data are available for other body sites across human populations or other species. We place the human gut microbiome into its evolutionary context across different modern populations with varying diets, lifestyles, and environmental exposures, and relate evolutionary patterns in the gut microbiome across the mammals to address several key questions. How do human microbiomes compare with our evolutionary ancestors? Are those patterns consistent with a common assumption that the microbiome evolves with the host? If so, what exactly is evolving in a microbiome and how? Does evolutionary history in the microbiome matter to human health and fitness? If so, how can we use evolutionary history to better understand the assembly and effects of the microbiome to the benefit of human health?To address these questions, we first describe the human gut microbiome and its contents. We then place this information in the context of our closest relatives, the primates, and more distant relatives, mammals. Then we discuss the consequences of modifying species-specific microbiomes, and some of the mechanisms underlying this process. Finally, we point the way to microbiome studies that can better take into account the evolutionary properties of hosts, microbes, and their symbioses to improve our knowledge both of the underlying biology and for practical applications in human and animal health.microbiota) of the large intestine as read out through the stool. This community harbors by far the greatest microbial biomass of any organ or surface of the human body. Each milliliter of the large intestine holds approximately 1011 microbial cells compared to 108 cells in the small intestine [Although the 6.5 meter human digestive tract consists of three organs—the stomach, small intestine, and large intestine—most human microbiome research focuses on the microbial community ? PFinally, to what degree are patterns of codiversification the result of adaptation, and to what degree can they be explained by neutral processes? It is often implied that humans and their microbes have adapted to each other, and that perturbing this relationship results in disease. Evidence suggesting non-neutral processes exists in a few cases , 58. We As we move forward, bringing these tools and this knowledge into medical microbiome research—taking an evolutionary medicine approach—can illuminate mechanisms underlying dysbiosis and allow us to harness the potential of the microbiome to improve human health.Microbiome: the biotic and abiotic habitat comprising the community of microorganisms associated with a particular environment or host. Sometimes synonymized with “microbiota”, though it has been argued the latter should be reserved for marker-gene-based descriptions of the biotic component of the microbiome [crobiome Metagenome: the collective genomes, or genomic components, of the microbiome. Empirically, metagenomes are investigated by random shotgun sequencing of the mixed community, rather than targeted sequencing of marker genes such as 16S rRNA.Hologenome: the genome of a host animal and its metagenome [tagenome –112. Contagenome , 114. Thtagenome , in partHolobiont: a host animal and its microbial associates. Two animals with identical genotypes but different microbial associates could express different “holobiont” phenotypes.Co-evolution: causally related, reciprocal changes in allele frequencies within populations of different organisms. This term has been used with conflicting or imprecise meanings for decades [process. Other previous uses have described patterns, which can be more usefully described with specific and discrete terms . decades ; we pref decades , which iCospeciation: one particular event in evolutionary history, in which the speciation of one organism itself causes the contemporaneous speciation of another organism. Cospeciation events over time can produce a pattern of codiversification; horizontal transmission can make this harder to detect, and other processes of adaptation and transfer can also produce tightly codiversified phylogenies in the absence of cospeciation [eciation , 119.Codiversification: a cophylogenetic pattern in which biologically associated organisms display predicted evolutionary histories more similar to one another than expected by chance. We advocate the special use of the term “codiversification”, distinct from coevolution or cospeciation, as a precise way to refer to a particularly interesting and frequently observed pattern. Codiversification might arise from a history of cospeciation, but could also result, for example, from the shared experience of population vicariance across a landscape inhabited by both organisms.Phylosymbiosis: a phenetic pattern of congruence between the phylogeny of a clade of host organisms and the similarities of their symbiotic microbial communities [munities . Phylosymunities , 99.Vertical transmission: acquisition of microbes directly from an organism’s parents. This conceivably happens either via transmission through the germline, as is frequently observed in insects, or subsequent interactions.Horizontal transmission: acquisition of microbes from sources other than an organism’s direct parents, such as the environment or from non-parental conspecifics.How can we know what our microbiomes looked like in the past? Were the microbiomes of our ancestors more diverse than our own, as predicted by the disappearing microbiome hypothesis ?Although comparing non-Western to Western microbiomes offers insights into how modern diets and medicine shape microbiome composition, no living population today carries an “ancestral” microbiome. Rather, turning to ancient samples such as coprolites –122, denAlthough coprolites or mummified intestinal contents give us the best snapshots of ancient gut microbiomes, typically these samples preserve poorly and not all profiled samples contain what we think of as gut microbes .Dental calculus, on the other hand, preserves quite well. Diversity of oral microbiomes decreased with the advent of agriculture, as observed from a series of samples dated between 7000 years ago to modern day . AdditioRecently, sequencing of Neanderthal dental calculus samples from two caves revealed oral microbiomes that differed according to inferred meat eating behavior at each site. The microbiota of putatively meat-eating specimens closely resemble hunter-gatherer populations, while non-meat eating specimens resemble forager-gathering chimpanzees . Given tMicrobiomes clearly impact host performance, and have changed along the branches of the animal evolutionary tree. Individual microbes, and their hosts, are clearly subject to evolutionary forces. But can a gut microbiome itself really be said to evolve?hologenome concept of evolution argue that the parallels between phenotypes induced in an organism by genes in its genome and those induced by microbes in a combined host–microbe system, or holobiont, are strong – sufficiently so that host–microbe systems can usefully be examined as an extension of the same evolutionary frameworks built to explore descent and modification of single organisms [Classically, evolution by natural selection requires three things: 1) phenotypic variation in a population, 2) differential reproductive success as a consequence of that variation, and 3) inheritance of said variation. Proponents of the rganisms , 114. Crrganisms , 115. MoThe most conceptually straightforward such mechanism—direct parental inheritance—may not be the most relevant to gut microbiomes. Extremely strict vertical transmission of microbes from parent to offspring would be necessary to link host and microbial genotypes sufficiently tightly for selection on one generation to change “holotype” frequency in the next. Some gut microbiomes may meet this criterion—in turtle ants, for example, gut bacteria are passed on to new adults, which then immediately grow a literal filter in their gut capable of keeping other microbes out ; some trIn a recent perspective, Doolittle and Booth  argue thFocusing on roles rather than players may also help in constructing alternative models to understand the fitness consequences of microbial associates that do show some degree of conservation through time—including the species-specific (or even codiversifying) microbes described from some mammalian guts. While the above model primarily interprets evolution in the microbiome in the context of host- (or holobiont-) level adaptation, real fitness consequences could also arise purely via random fixation of nearly neutral mutations in hosts and sets of species-specific microbes Fig. . Rather


This paper describes the means by which a United States National Institute on Drug Abuse (NIDA)-funded cooperative, Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS), utilized an established implementation science framework in conducting a multi-site, multi-research center implementation intervention initiative. The initiative aimed to bolster the ability of juvenile justice agencies to address unmet client needs related to substance use while enhancing inter-organizational relationships between juvenile justice and local behavioral health partners.The EPIS  framework was selected and utilized as the guiding model from inception through project completion; including the mapping of implementation strategies to EPIS stages, articulation of research questions, and selection, content, and timing of measurement protocols. Among other key developments, the project led to a reconceptualization of its governing implementation science framework into cyclical form as the EPIS Wheel. The EPIS Wheel is more consistent with rapid-cycle testing principles and permits researchers to track both progressive and recursive movement through EPIS. Moreover, because this randomized controlled trial was predicated on a bundled strategy method, JJ-TRIALS was designed to rigorously test progress through the EPIS stages as promoted by facilitation of data-driven decision making principles. The project extended EPIS by (1) elucidating the role and nature of recursive activity in promoting change (yielding the circular EPIS Wheel), (2) by expanding the applicability of the EPIS framework beyond a single evidence-based practice (EBP) to address varying process improvement efforts (representing varying EBPs), and (3) by disentangling outcome measures of progression through EPIS stages from the a priori established study timeline.The utilization of EPIS in JJ-TRIALS provides a model for practical and applied use of implementation frameworks in real-world settings that span outer service system and inner organizational contexts in improving care for vulnerable populations.NCT02672150. Retrospectively registered on 22 January 2016. Regardless of service sector or clientele, any initiative aimed at changing public sector systems of care requires careful consideration of potentially challenging factors that commonly impact implementation efforts. Common challenges include structural and cultural impediments to change within organizations, personnel aversion to the adoption of new practices, inadequate information systems, and lack of coordination among agencies within an existing system. The field of implementation science has emerged so that such factors can be identified and addressed in a systematic fashion and, where possible, successfully overcome. Moreover, implementation science permits researchers examining change within complex systems to make critical study design decisions informed by a guiding conceptual framework.Exploration, Preparation, Implementation, and Sustainment (EPIS)  can be provided within a single agency such as a probation department or drug court. However, this approach is rare. Often, youths who could benefit from receiving several types of services must interact with multiple service agencies that operate independent of the juvenile justice (JJ) entity. For instance, youth commonly interact with probation officers and clinical staff who work within independently functioning organizations such as probation departments or behavioral health (BH) agencies. This model represents a possible gap in system-organization relationships and organizational networks. Consequently, services are fragmented, and youth may “fall through the cracks” when transitioning between different service systems and provider organizations.Distinctive characteristics among these agencies may also obstruct efforts to improve service coordination at multiple levels , each of which recruited one or more state or regional JJ agency leaders to participate as full partners in the planning, execution, and evaluation of the studies . During this two-day meeting, several frameworks were carefully considered based on a then-recent review by Tabak and colleagues  in which it was to be applied. Because agency staff would themselves serve as the change agents, it was important that the selected model avoid imposing complexity that would overwhelm or burden them. JJ partner perspectives were critical in estimating the degree of burden likely to occur at research sites due to the chosen implementation model, thereby underscoring the value of research/practitioner relationships from the outset. EPIS provides a comprehensive four-stage framework that is readily understood by organizational actors who are asked to draw on their local knowledge of agency-level and system-level dynamics to create sustainable change.EPIS was selected as a guiding framework prior to the design of the JJ-TRIALS study, and therefore drove the selection, design, and timing of every essential component of the study (see detailed intervention protocol) , dynamic processes were overlaid on the linear application. This discussion focused on the degree of flexibility in the model and how it could best reflect the complex and dynamic nature of the participating JJ systems. At the suggestion of the engaged JJ partners, EPIS was adapted from its original linear format with a clearly delineated start point (Exploration) and end point (Sustainment) to a circular wheel-like model see Fig. . Thus, wThe EPIS Wheel therefore depicts the circular nature of rapid-cycle testing , wherein persistent enhancements and refinements in organizational functioning are encouraged. Furthermore, several stakeholder spokes were added to highlight and represent diverse interests relevant to the JJ context throughout the process of phased change already included in EPIS: (1) advocacy groups, (2) researchers, (3) community-based organizations, and (4) service systems. These spokes conceptualize the change process as dynamic in nature, whereby efforts continually unfold as aspects of the inner and outer contexts evolve and stakeholders at various levels become involved in implementation of goals and objectives. Changes in the system, the organization, or the specific needs of youth can impact the feasibility of conceived implementation efforts. For example, turnover among staff who are responsible for change can slow progress, and new leadership can shift priorities or redefine objectives so that resources for implementation are no longer available. When these developments occur, the stakeholders must naturally revisit previous stages, revise plans or even explore new options.The outer rim of the EPIS Wheel captures this dynamic movement in either a progressive (forward/linear) direction or a recursive  direction as “problem-solving orientation” and “collaboration-negotiation-coalescence” that may characterize the nature of successful community-academic collaborations . The Goal Achievement Training occurred over a two-day onsite meeting during which RCs provided support to agencies for (1) identifying realistic goals and actionable steps for implementing new service practices along the Cascade as informed by the site feedback report, (2) using DDDM to inform progress toward site goals and steps, and (3) sustaining changes in delivery of substance use services. Subsequent to goal selection, sites were asked to develop an action plan, which specified the concrete, measurable steps required to attain their goal. The conclusion of training signaled the close of the Baseline period, and thus the end of the identical support strategies across the 36 sites. The study design specified that successful selection of a goal and initiation of work on an action plan during training would signal entry into the Implementation stage of EPIS, whereas sites that did not select a goal would remain in the Exploration stage as the Experiment period began. Ultimately, all sites were successful in goal selection and initiated work toward defining steps during training. Because the study periods are conceptualized as separate from the EPIS stages, this project tracks how various intervention components affect movement through EPIS.At the close of the Baseline period, all sites were asked to work toward their site identified goals (implementation of new service practices) and to utilize JJ-TRIALS tools and resources for the following 12-month Experiment period. For example, sites were encouraged to apply DDDM techniques including rapid-cycle testing Deming,  whereby To test the primary hypotheses (comparing the two implementation intervention strategies), half of the sites (those randomized to the enhanced condition) received access to a researcher-based facilitator during the Experiment period. Facilitators’ roles included cultivating ongoing workgroup discussions, supporting and encouraging the use of data to inform agency decisions and to monitor and inform site goals, providing guidance in progress toward site identified process improvement plans, and promoting sustainment of site changes such as documenting changes in site policy and procedures and developing plans to roll out piloted service revisions site-wide , work toward sustainment of enacted changes, implement changes agency-wide , and/or identify and work toward other site-identified goals to address unmet service needs among youth on community supervision. Utilization of DDDM tools toward identified goals occurred independent of researcher-based facilitation in all sites, which allowed natural observation of site continued engagement in process improvement activities.As with the timing and selection of implementation strategies, the EPIS framework informed the development and articulation of research questions and hypotheses. In addition to primary hypotheses—examining the differential effect of the strategies bundle on sites with (enhanced condition) and without researcher-based facilitation (core condition)—using EPIS as a guiding framework stimulated exploratory research questions regarding movement across and within EPIS stages, as well as how that process impacted implementation outcomes . For instance, exploratory questions inspired by a linear application of EPIS included “Relative to core, does the enhanced condition increase the likelihood that sites will implement their action plans by the end of the Experiment period?” and “Is implementation of action plans associated with improved outcomes during the Post-Experiment period?” It was hypothesized that without support in the form of facilitation, core sites may get “stuck” at the Preparation stage and not move fully into the Implementation or Sustainment stages. Questions inspired by a dynamic application of EPIS, highlighting the recursive process of change, included “Relative to core, does the enhanced condition improve workgroup perceptions of the value of DDDM?” and “If DDDM is used, does it promote improved outcomes during the Post-Experiment period?” Rapid-cycle testing can be a lengthy and burdensome process, especially if workgroup members become discouraged when progress diminishes during recursive activity. Facilitation may help keep workgroups on target and help maneuver such challenges.Other questions inspired by dynamic applications included “Are sites that engage in more recursive movement  more successful in increasing youth services?” and “Do workgroups that function collaboratively with stakeholders at various levels of the partnering agencies  revise plans more substantially and implement more sustainable plans compared to workgroups with representation from a single agency  or single level ?” Expanding beyond examination of linear movement provided a novel opportunity to test the relationship between recursive activity within or across EPIS stages, engagement in process improvement activities , attitudes toward continued use of process improvement methods, and sustainment of new practices.which domains/variables are most important to measure at which points over time as change efforts unfold. Design and measurement choices clearly needed to be made a priori but, in some cases, modified throughout the project . Prior empirical research can certainly help guide these decisions and assess different tradeoffs to some degree, depending upon the specific process improvement goal and the setting under consideration. Consequently, the central research questions guiding JJ-TRIALS and the project’s data collection procedures were ultimately informed by EPIS.A measurement design challenge inherent in working with an implementation study involving varying process improvement goals  and assessment of change across all four EPIS stages involved how to predict and articulate Linear measurement applications specific to JJ-TRIALS were based on Aarons’ original conceptualization  posed significant measurement challenges. This allowance meant that site-selected EBPs would also vary, and represented a departure from studies applying EPIS to the implementation of a single EBP across multiple sites  in all sites; the transition from Implementation to Sustainment was differentially supported by RC intervention activities  based on random assignment to condition. Therefore, this project allowed transition to occur along two dimensions, study activities , and site-initiated activities . Allowing a second dimension, namely site-initiated activities, to monitor transitions, provided for a flexible application and empirical test of the EPIS framework and natural variation in the speed through which sites addressed action steps and accomplished their goal. It was expected that some sites, especially the enhanced sites, would transition to the Sustainment stage prior to the end of the 12-month facilitation period.Beyond the identification of universal activities common across site selected EBPs, it was crucial to measure objective criteria  that could then be used to signal transition between EPIS stages. Developing objective markers of the transition between EPIS stages rather than relying on assumptions about how long each stage should last  was one of the major methodological issues that had to be resolved in applying and rigorously testing the EPIS framework. As indicated in Fig. The a priori designations for signaling transitions between EPIS stages were crucial from a project management perspective. The JJ-TRIALS design allowed for cross-site variations in many ways, but it was also structured to ensure that the overall study moved forward regardless of whether sites met their goals. For example, if a site failed to reach their goal by the end of the Experiment period, this outcome was treated as data rather than a justification for extending the amount of time that site was tracked or extending facilitation that was provided to enhanced sites.As is demonstrated above, the JJ-TRIALS Project with 36 sites, situated across seven states and using EPIS as a guiding framework has successfully conducted one of the largest implementation studies to date. A design challenge inherent to multi-site, multi-stage projects targeting strategies at each successive stage, such as in the JJ-TRIALS project, was the balance between intervention and data collection comprehensiveness and experienced participant and research burden. For instance, while measuring recursive movement through the EPIS model is a key contribution of this project, to minimize site burden, limitations were set with regard to frequency of data and level of detail on activities collected. Data were captured on a monthly basis, rather than in a real-time log of activities; possibly resulting in some loss of information, recall bias, and data inconsistencies within and across sites. Along the same lines, to avoid undue burden, this project restricted estimated implementation costs to investment in the intervention being implemented. Other possible implementation costs  associated with activities across each of the EPIS stages, were seen as too laborious to accurately collect for this project. While there were few approaches for examining implementation costs at the inception of JJ-TRIALS (Liu et al., An additional challenge requiring careful consideration for the JJ-TRIALS project was the early emphasis on allowing sites to select EBPs that were responsive to context-specific needs. This focus on context-specific needs was critical for understanding adaptations and tailoring analyses for relevance to each local context. The study design, therefore, placed greater emphasis on tracking process outcomes and resulting agency level EBP adoption, rather than an emphasis on monitoring fidelity; adaptation to promote fit (Chambers & Norton, EPIS is a well-established model for understanding, researching, and supporting the implementation of new practices. It was initially designed for implementation science research focused on public sector services including mental health and child welfare, and similarly organized systems such as substance use disorder treatment (Aarons et al., The JJ-TRIALS project represents an ambitious attempt to improve services for justice-involved youth in a number of juvenile justice systems across the United States through a structured organizational and system change initiative. JJ-TRIALS also represents an attempt to advance implementation science. The deliberate and comprehensive integration of a conceptual model into every essential aspect of the JJ-TRIALS study design from inception to completion allowed for a salient examination of implementation, service, and client outcomes. Future efforts will empirically examine the EPIS framework through hypotheses on linear and dynamic movement in process improvement planning. Additional efforts are underway to examine similar processes through a JJ-TRIALS pilot study to promote expansion of HIV/STI education and testing services among juvenile justice and partnering public health agencies. It is the hope that this paper will not only offer a valuable example of how to incorporate a conceptual framework into a complex study design, but also as a platform for rigorously testing models such as EPIS so that they can more effectively inform and advance future implementation efforts.


Twenty years have passed since the dysconnection hypothesis was first proposed . In that time, neuroscience has witnessed tremendous advances: we now live in a world of non-invasive neuroanatomy, computational neuroimaging and the Bayesian brain. The genomics era has come and gone. Connectomics and large-scale neuroinformatics initiatives are emerging everywhere. So where is the dysconnection hypothesis now? This article considers how the notion of schizophrenia as a dysconnection syndrome has developed – and how it has been enriched by recent advances in clinical neuroscience. In particular, we examine the dysconnection hypothesis in the context of (i) theoretical neurobiology and computational psychiatry; (ii) the empirical insights afforded by neuroimaging and associated connectomics – and (iii) how bottom-up (molecular biology and genetics) and top-down (systems biology) perspectives are converging on the mechanisms and nature of dysconnections in schizophrenia. In other words, the fact that psychosis can be induced by simply changing the neuromodulatory status of synaptic integration suggests that the anatomical and neurodevelopmental characteristics of schizophrenia are consequences not causes of the underlying pathophysiology. Furthermore, while synaptic abnormalities can explain aberrant neurodevelopment , the converse is less obvious. Clearly, this is a rather polemic argument: for instance, ketamine could just produce a phenocopy or the pathophysiology at play may be manifest throughout development, affecting both synaptic function and neurogenesis  influence of intrinsic and extrinsic (long-range) connectivity. It proposes that the key pathophysiology lies in the interactions between NMDA receptor function and modulatory neurotransmitter systems. While many (synaptic) theories of schizophrenia postulate a central role for NMDA receptors , the dys3false inference – and how this false inference is realized neurophysiologically.There are many computational perspectives that could be called upon to characterize psychopathology. These range from neural network and dynamical systems theory to reinforcement learning and game theory. However, these frameworks do not address the quintessential aspect of schizophrenia; namely, the production of false beliefs. The symptoms and signs of schizophrenia are, almost universally, attended by abnormal beliefs and their behavioral sequelae; for example, paranoid ideation, delusions, hallucinations, and so on. This calls for a theoretical framework that explains A recent paradigm shift in cognitive neuroscience provides exactly the right sort of theory that allows one to talk about false beliefs – and understand how these arise from synaptic pathophysiology. Cognitive neuroscientists now view the brain as a statistical organ that generates hypotheses or fantasies that are tested against sensory evidence. This perspective can be traced back to Helmholtz and the notion of unconscious inference . In the 3.1Modern formulations of Helmholtz's ideas usually appeal to theories such as predictive coding . Predictdog). The simplest encoding corresponds to the expected value or expectation of a (hidden) cause. These causes are referred to as hidden because they have to be inferred from their sensory consequences. In short, predictive coding represents a biologically plausible scheme for updating beliefs about the world using sensory samples. In predictive coding, neuronal representations in higher levels of cortical hierarchies generate predictions of representations in lower levels. These top-down predictions are compared with representations at the lower level to form a prediction error . The ensuing mismatch signal is passed back up the hierarchy, to update higher representations . This recursive exchange of signals suppresses prediction error at each and every level to provide a hierarchical explanation for sensory inputs. In computational terms, neuronal activity is thought to encode beliefs about states of the world that cause sensations  precision. This represents a subtle but generic problem that the brain must solve, where the solution may rest on modulating the gain or excitability of neuronal populations reporting prediction error  explanation for many aspects of functional anatomy and perception. However, simply predicting the content of our sensations is only half the story. There is something else that we have to predict; namely, the confidence or ertainty . In otheon error .gain of prediction errors that compete to update expectations. Empirical evidence suggests that this boosting or precision-weighting of prediction errors is a central computational process throughout the brain  have so many synaptic gain control mechanisms; such as NMDA receptors and classical neuromodulatory receptors like D1 dopamine receptors . Further4So why is the encoding of uncertainty or precision so important for schizophrenia? If schizophrenia is a brain disorder – and the brain is an organ of inference – then its psychopathology must be manifest as a failure of prediction or inference. Analyses of false inference that emerges under failures of predictive coding all point to one abnormality; namely, a failure to properly the encode precision of prediction errors . There i4.1failure to attenuate sensory precision; in other words, an inability to modulate the gain of sensory prediction errors, relative to higher-level prediction errors that optimize prior beliefs about the causes of the sensory stream. A failure to attenuate sensory precision, from a psychological perspective, means one cannot ignore stimuli and call upon prior beliefs or predictions. In brief, this means that everything is surprising  because it cannot be predicted. This single computational failure can explain a wide range of signs and symptoms in schizophrenia. For example, if everything is surprising, then it would be difficult to elicit oddball, violation or omission responses – as measured electrophysiologically. This explains impoverished mismatch negativity responses in schizophrenia . This has led some to suggest that state abnormalities reflect a compensation for overly precise sensory prediction errors. For example, if one reduces sensory precision it is relatively easy to simulate hallucinosis . This fo4.2active inference . This provides a straightforward explanation for some trait abnormalities in schizophrenia; both in terms of psychomotor poverty and in terms of psychophysics. Psychophysically, the attenuation of sensory precision is known as ade acts . A failuade acts . We can ade acts .delusions are hallucinations about agency or action. This has an interesting corollary: it means that delusions must necessarily entail false beliefs about behavior, action, agency and intention – of the self or others. Furthermore, rational beliefs formed under irrational precision may necessarily involve outside agencies that are antagonistic, leading to a formal understanding of paranoid ideation.A key insight afforded by this (active inference) account of false inference in schizophrenia is that similar mechanisms underlie hallucinations and delusions: namely, a compensatory increase in the precision of prior (high-level) beliefs, relative to the (unattenuated) precision of (low-level) sensory evidence. This suggests that Computational studies of hallucinations and delusions are still in their infancy; however, they already speak to some fundaments of false inference. Key among these is the relative precision at different levels of the cortical hierarchy. At present, consensus suggests that delusions are associated with unduly precise prior beliefs deep within the hierarchy, leading to recalcitrant explanations for – and attention to – sensory evidence. See  for a reIn summary, to explain false inference in schizophrenia , we are drawn to modern versions of Helmholtz's formulation of perception as (unconscious) inference. When deconstructed in terms of neuronally plausible process theories – such as predictive coding – we arrive at the same conclusion that underlies the dysconnection hypothesis; namely, an aberrant modulation of synaptic gain. This convergence equips the dysconnection hypothesis with a formal state theory  and a process theory (aberrant precision or gain control in predictive coding). The ensuing false inference is explained not in terms of an inability to predict sensory content but a failure to encode the relative confidence that should be placed in sensory evidence, relative to prior beliefs. This can produce a pernicious form of false inference that has been considered at a number of levels; from the genesis of delusions and hallucinations  through 4.3Having a process theory is important because it provides mechanistic predictions that can be tested empirically. Furthermore, it grounds physiological (synaptic) theories of schizophrenia in a functional framework; thereby linking pathophysiological explanations to functional deficits and the patient's beliefs and experiences. Dysfunctional integration at the synaptic level fits comfortably with earlier theories framed in terms of signal-to-noise . Furthersynchronous gain. The mechanism here is simple: fast synchronous exchange of neuronal signals increases postsynaptic conductance, synaptic rate constants and postsynaptic gain , where functional connectivity is defined as the statistical dependence between remote neurophysiological measures. As such, they only provide circumstantial evidence for dysconnection. In other words, they are a compelling ‘smoking gun’. Definitive evidence for systemic dysconnectivity at the synaptic level requires estimates of effective connectivity . In fMRI, estimating effective (directed) connectivity is difficult due to hemodynamic variability across regions; this is usually resolved by biophysically informed state space models like dynamic causal modelling (DCM). Dynamic causal modelling has, in principle, the potential to drill down on very specific synaptic processes implicated in schizophrenia. For example, DRD2 and AKT1 polymorphisms in healthy subjects – implicated in DRD2 signalling – have a selective effect on directed prefrontal-striatal connectivity, while the same polymorphisms alter the dose-response effects of anti-psychotic drugs on cognition in schizophrenia .In recent years, DCM studies of schizophrenia have started to appear . Almost These fMRI studies of disconnection are consistent with a failure of top-down modulation  of postsynaptic gain or precision in DCM studies of electrophysiological data; especially studies of the mismatch negativity and related paradigms . But whaThe dysconnection hypothesis suggests a failure of functional integration in distributed but circumscribed neuronal systems that are particularly dependent upon neuromodulatory afferents ; e.g., fOver all studies, significant reductions were present in two regions: the left frontal deep white matter and the left temporal deep white matter. The first region, in the left frontal lobe, is traversed by white matter tracts interconnecting the frontal lobe, thalamus and cingulate gyrus. The second region, in the temporal lobe, is traversed by white matter tracts interconnecting the frontal lobe, insula, hippocampus-amygdala, temporal and occipital lobe. This suggests that two networks of white matter tracts may be affected in schizophrenia, with the potential for ‘disconnection’ of the gray matter regions which they link.”“5.1In summary, the evidence for a systemic dysfunctional integration from non-invasive studies of schizophrenia is overwhelming. Much of this evidence is circumstantial and predicated on measures of functional connectivity; i.e., correlations or coherence among measures of neurophysiology. The consensus of these findings is a functional dysconnection involving prefrontal cortex and key subcortical  and associative cortical  nodes. Recent  modelling of intrinsic (within source) and extrinsic (between source) connectivity suggests a specific failure of intrinsic gain within the prefrontal cortex or descending modulation of synaptic efficacy in hierarchically subordinate structures. So what might mediate these neuromodulatory failures?6In this section, we revisit the dysconnection hypothesis from the perspective of genetic studies. We review the evidence that the genetic alterations in schizophrenia have pathogenetic implications for NMDA receptors and their interactions with neuromodulatory transmitters. With the discovery of the DISC1 translocation in a large family with high penetrant psychosis in 1990 , it was d-serine, a co-agonist at NMDA receptors), the GluR1 subunit of AMPA receptors (GRIA1), and various genes encoding calcium channels critical for plasticity at glutamatergic synapses. Further genes identified by this study implicated receptors whose activation is known to modulate NMDAR function, including the D2 receptor (DRD2) and the metabotropic glutamate receptor 3 gene (GRM3).Despite the large number of associations, SNPs only account for up to 23% of the variation in liability for schizophrenia , with odBeyond SNPs, recent advances in genomics have allowed new sorts of genetic variation to be examined. Application of exome capture and sequencing has identified rare, putatively damaging mutations in multiple genes related to NMDAR function in multiplex families . In addiCOMT gene – of relevance for dopamine metabolism (Copy number variants (CNVs) have also been investigated in psychosis. For example 25–30% of adult patients with 22q11.2 deletion syndrome (DiGeorge Syndrome), a deletion which includes the tabolism  – suffertabolism , making tabolism . Again, tabolism .These findings have refined our understanding of the genetic architecture of schizophrenia . Moving 6.1Recent advances in the genetics of schizophrenia suggest a central role of the NMDA receptor and its interactions with modulatory transmitters in the pathogenesis of schizophrenia. A risk [CACNA1C] allele was associated with decreased outflow of information from medial frontal gyrus, which was significantly more marked in patients than in their unaffected relatives and healthy controls”  proteins mediating the neuromodulation of synaptic efficacy or postsynaptic gain in specific brain systems; particularly prefrontal systems.•We think that this molecular pathology arises from an abnormal response of the NMDA receptor to specific (e.g. dopaminergic) neuromodulatory receptor activation. This is important because the NMDA receptor mediates activity-dependent changes in postsynaptic gain and subsequent changes in synaptic efficacy.•The consequences of this abnormal neuromodulation can be diverse; ranging from dendritic and cytoarchitectonic changes, through to activity-dependent changes in myelination, which can be observed microscopically (post-mortem) and macroscopically (using non-invasive neuroimaging).•The physiological consequences of abnormal gain control are also expressed in terms of a failure to modulate synchronous gain and abnormalities in the coherence of neurophysiological measurements. It is likely that this involves secondary abnormalities in GABAergic neurotransmission that can be summarized as a failure to optimize excitation-inhibition balance or cortical gain control.•The psychological consequences of failing to modulate synaptic gain can be understood by appreciating that the brain generates hypotheses or beliefs that best explain sensory evidence. A crucial aspect of this process is the encoding of precision or uncertainty that is necessary to select the salient information that updates and contextualizes our beliefs. This attentional selection depends on modulating synaptic gain.•A failure of neuromodulatory mechanisms that control synaptic efficacy or postsynaptic gain corresponds, functionally, to an inability to augment (attend) or attenuate (ignore) the precision of sensory evidence, relative to the precision of beliefs about the causes of sensory cues. This can lead to false inference  that may reflect the brain's attempt to compensate for a pernicious and fundamental attentional failure.•The particular  systems implicated in the pathophysiology of schizophrenia may be particularly compromised at later stages of neurodevelopment – or environmental factors that could induce a circular causality .•A further consequence of false inference is compromised learning that rests on activity-dependent associative plasticity. This means that false inference associated with the positive symptoms of schizophrenia may go hand-in-hand with impaired learning and associated cognitive difficulties.Perhaps the best way to conclude is to think about how we would describe schizophrenia to a patient or relative. On the basis of the above, one could plausibly say:Clearly, this summary is rather speculative: to close the explanatory gap between pathophysiology at the molecular (synaptic) level and the psychopathology experienced by patients, we still need to identify the links between abnormal synaptic integration, polygenetic predisposition, epigenetics, region-specific gene expression and the implications for hierarchical inference in the brain. Such studies are now starting to appear; e.g.,  and one Wellcome Trust (Wellcome Trust grant no 088130/Z/09/Z). Drs Stefan and Siemerkus are supported by the University of Zurich and the René and Susanne Braginsky Foundation.Drs Friston and Brown were supported by the All authors contributed to the conceptual material described in this review. All authors contributed to the literature review and subsequent synthesis. Authors contributed to and have approved the final manuscript.All authors declare they have conflicts of interest.