Because of the COVID-19 pandemic, caused by SARS-CoV-2, many individuals experience post-infection long-lasting symptoms, namely post-COVID syndrome or Long COVID ^[1][2][1,2]. Long COVID is characterized by the persistence of exhausting fatigue, neurocognitive difficulties such as mental fog, muscle pain, and weakness, as well as depression, lasting beyond the 3–12 weeks following SARS-CoV-2 infection [3]. According to Naik et al., the most common symptoms are myalgia (10.9%), fatigue (5.5%), shortness of breath (6.1%), cough (2.1%), insomnia (1.4%), mood disturbances (0.48%), and anxiety (0.6%) ^[4][5][4,5]. The persistence of the symptoms seems to be linked to immune dysregulation due to harmful inflammation, although the exact causes are still unknown ^[6][7][6,7]. Recently, a huge number of studies have reported immune abnormalities, such as an increase in the innate immune system activity, chronic fatigue/myalgic syndrome, encephalomyelitis [8], fibromyalgia [9], cognitive dysfunction [10], depression, and other mental health disorders ^[11][12][13][11,12,13]. Concerning the latter disorders, neuroinflammation may play a key role in the onset of symptoms, through either an activation of microglia or auto-immune reactions ^[14][15][14,15]. Indeed, Long COVID often presents with “brain fog”, which is characterized by low energy, concentration problems, disorientation, and difficulty finding the right words ^[16][17][16,17]. However, long-term psychological, cognitive, or adverse mental health consequences of COVID-19 have recently begun to be recognized. Hampshire et al. [18] showed that COVID-19 could have a multi-domain impact on human cognition, as assessed using psychometric subtests. In particular, people who had recovered from the infectious disease, including those no longer reporting symptoms, may exhibit significant cognitive deficits as compared to controls, when controlled for age, gender, education level, income, racial–ethnic group, pre-existing medical disorders, tiredness, depression, and anxiety. Moreover, Ocsovszky et al. [19] found a positive correlation between the level of depressive symptoms and anxiety in a Long COVID non-hospitalized cohort. Depression and anxiety have been shown to have a negative impact on symptom perception and also contribute to a higher number of symptoms in a non-hospitalized sample, suggesting a bi-directional interconnection between the clinical and psychological factors ^{[20][21][22][23]}[20,21,22,23]. Therefore, multidisciplinary rehabilitation interventions are necessary to better manage individuals with Long COVID. In fact, cognitive rehabilitation, including compensatory and metacognitive strategies, which are usually administered to patients with brain injury, can be also applied to the Long COVID population ^[24][25][24,25].

2. Neurological Manifestations of Long COVID

The neurological manifestations (NMs) of Long COVID remain an outstanding issue since the pathogenic mechanisms are poorly understood despite the high prevalence of the symptoms. The most commonly reported NMs are fatigue (72%), muscle aches/myalgia (57%), and headache (53%) [26]. Orrù G. et al. [27] also included loss of smell and loss of concentration, as well as insomnia and reduced quality of life. However, it has been pointed out that anosmia and dysgeusia are more commonly related to the acute COVID-19 infection as these specific symptoms generally resolve [28]. Conversely, symptoms such as headaches, anxiety, depression, brain fog, fatigue, and insomnia are more likely to belong to the post-infection syndrome. NM onset may be due to an association between biological and psychological factors. In fact, SARS-CoV-2 could remain in brain tissue long-term, affecting neuronal loss over time, in association with systemic inflammation and cerebrovascular changes, as recently demonstrated by Desai et al. [29]. Notably, inflammation may induce neuron injury/damage through the release of the cytotoxic and chemotactic mediators, activating the surrounding microglial cells and intensifying the microglia-mediated neuroinflammation [30]. This cytotoxins release causes neuronal loss and neurodegeneration, accounting for the cross-talk between the neurons and glial cells in the neuroinflammation status [31]. To overcome these negative implications, steroids have been successfully used, especially in the acute phase and in the most severely affected patients [32]. Moreover, to counteract prostaglandin-mediated inflammation, non- steroidal anti-inflammatory drugs may be used in different stages of the disease [33]. Some researcheuthors considered the use of Palmitoylethanolamide (PEA) in the treatment of Long COVID, showing that the compound could resolve these inflammatory processes, reducing the progression of chronic inflammation and promoting positive effects on the neurological system [34]. It has been highlighted that the peripheral activation of the trigemino-vascular system, through the inflammatory cytokine storm, is strictly involved in the development of headaches [35]. Headache, from continuous mild pain to severe migraine, seems to be one of the most common and persistent COVID-19 sequelae, and it is often accompanied with trigeminal neuralgia. Neuropathic pain due to Long COVID is underestimated compared to the other symptoms, although the main clinical features of neuropathic pain in COVID-19 patients, i.e., a prickling sensation (defined as a sensation of electric shock, burns, paresthesia, and hyperalgesia), have been well described ^[36][37][36,37]. Many patients complained of subtle cognitive impairment and behavioral changes that may be difficult for them to describe. These symptoms are often collectively referred to as “brain fog” or “mental clouding” [38]. However, the correlation between these self-reported symptoms and objective dysfunctions remains an unclear question. Di Stadio et al. [39] investigated the possible correlation between mental clouding and olfactory dysfunction: they found that the former might interfere with the capacity of the individual to identify odors, indirectly affecting olfactory function. In addition, subjects who suffered from mental clouding, headache, or both presented a more severe olfactory dysfunction compared to those patients without neurological complaints.

3. Cognitive Dysfunctions, Psychiatric Symptoms, and Behavioral Alterations

Cognitive dysfunctions are becoming the most popular symptoms in the research of Long COVID. In fact, cognitive symptoms have been reported in around 70% of the subjects ^[40][41][40,41]. Davis et al. [42] showed a high impact of post-COVID-19 cognitive dysfunction and/or memory impairment in daily working abilities, accounting for 86% of the sample affected. Guo et al. found a similar prevalence of cognitive symptoms: 77.8% of the patients presented difficulty in concentrating, 69% brain fog, 67.5% forgetfulness, 59.5% tip-of-the-tongue word-finding problems, and 43.7% semantic disfluency (saying or typing the wrong word) [43]. In addition, it has been shown that cognitive symptoms are more likely to develop in subjects affected by fatigue, cardiopulmonary, neurological, and autoimmune symptoms. However, in current clinical practice, it is very difficult to understand and define the “type and severity of the self-reported cognitive deficits”, such as brain fog and difficulty concentrating, and consequently to more objectively measure cognitive performance. Indeed, most studies focused on the prevalence of cognitive alterations due to Long COVID, but not on the psychometric tools to measure the cognitive domains affected by the post-SARS-CoV-2 infection [44]. To overcome this issue, Alemanno et al. measured the cognitive abilities of patients in the COVID-19 post-acute phase that had experienced severe disease, using the Montreal Cognitive Assessment (MoCA). They have observed that 80% of patients reported cognitive alterations, especially in memory abilities, executive functioning, and language skills [45]. It has been observed that 33% of individuals in an intensive care unit showed a dysexecutive syndrome associated with inattention, disorientation, and reduced planning movements in response to the verbal indications [46]. Hosp et al. found a possible correlation between the cognitive dysfunctions and neurological abnormalities revealed with positron emission tomography, showing a predominant frontoparietal hypometabolism that correlated with poor MoCA scores [47], with lower scores in verbal memory and executive functions. However, these studies are limited to severely ill and old-age patients, and it is very challenging for clinicians to determine the nature of these dysfunctions and whether they are specific to COVID-19 or are more a-specific, such as a general consequence of acute respiratory distress. Indeed, some survivors of critical disease are recognized as experiencing long-term cognitive loss [48], particularly if they experience delirium ^[49][50][49,50]. In this context, it is important to know whether these deficits may also involve younger populations, as demonstrated by Almeria et al. in patients aged 24–60. This researchtudy reported that patients with neurological sequelae had lower performance in attention, memory, and executive function, suggesting an association between symptomatology and cognitive deficits [51]. Recent literature regarding the long-term neuropsychiatric sequelae of COVID-19 focused on self-reported symptoms through questionnaires administered either in-person or by telephone interviews ^[52][53][54][52,53,54]. Notably, Long COVID has been found to cause anxiety and depression symptoms as well as other neuropsychiatric and cognitive sequelae ^{[55][56][57][58][59]}[55,56,57,58,59]. Indeed, the incidence of anxiety, depression, and post-traumatic stress was 42%, 31%, and 28%, respectively, in an Italian sample [60]. Considering the alarming impact of COVID-19 on mental health, Clemente et al. investigated the correlation between the psychological status of patients who had recovered from the SARS-CoV-2 infection and their inflammatory status, showing that survivors are at risk of developing psychiatric sequelae, such as anxiety, depression, and somatization symptoms, as well as sleep disorders ^[61][62][63][61,62,63]. An interesting association has also been demonstrated between high ferritin blood levels and sleep disturbances, stress, depression, and suicidal ideation ^[64][65][64,65]. To summarize, the SARS-CoV-2 epidemic was associated with psychiatric and cognitive complications, as confirmed by several researchers ^{[66][67][68][69]}[66,67,68,69], and patients with preexisting psychiatric disorders reported the worsening of previous symptoms ^{[70][71][72][73]}[70,71,72,73]. These findings could support the idea that those who have experienced the COVID-19 infection may be at a higher risk for neurodegeneration and dementia. In fact, COVID-19-related cardiovascular and cerebrovascular disease may also contribute to a higher long-term risk of cognitive decline and dementia in recovered individuals [74]. Moreover, a vast number of studies showed that obesity and diabetes have been associated with worse outcomes during the COVID-19 infection. In fact, people with obesity have an increased prevalence of diseases such as renal insufficiency, cardiovascular diseases, Type 2 diabetes mellitus, certain types of cancers, and a significant degree of endothelial dysfunction. These conditions are major risk factors for the disease severity and mortality associated with COVID-19 ^[75][76][75,76]. In particular, Vimercate et al. (2021) have shown that obesity is associated also with worse Long COVID symptoms such as respiratory diseases and hypertension, suggesting that being affected by overweight or obesity is associated with prolonged symptoms after resolution [77]. Today, limited evidence has shown that the clinical and socio-demographical features of the patients (such as the number of symptoms in the first week, age, and sex) before the COVID-19 infection play a key role in the prediction of Long COVID’s duration [78]. Notably, Bellou et al. have investigated the association of 91 unique prognostic factors, divided into seven different categories, including demographic and anthropometric individual characteristics, biomarkers, symptoms, clinical signs, medical history and comorbid diseases, and medications, thus facilitating the selection of candidate predictors for a prognostic model [79]. In this context, Wang et al. found that psychological distress before the COVID-19 infection, including depression, anxiety, worry, perceived stress, and loneliness, was associated with a 32–46% increased risk of Long COVID [80]. For all these reasons, urgent in-person neuropsychological and neuropsychiatric assessments on Long COVID individuals are needed.