Short Term Memory Impairment

Article Author:
Marco Cascella
Article Editor:
Yasir Al Khalili
Updated:
8/16/2019 9:08:48 AM
PubMed Link:
Short Term Memory Impairment

Introduction

Short-term memory (STM), also referred to as short-term storage, or primary or active memory indicates different systems of memory involved in the retention of pieces of information (memory chunks) for a relatively short time (usually up to 30 seconds). In contrast, long-term memory (LTM) may hold an indefinite amount of information. The difference between the two memories, however, is not just in the 'time' variable but is above all functional. Nevertheless, the two systems are closely related. Practically, STM works as a kind of “scratchpad” for temporary recall of a limited number of data (in the verbal domain, roughly the George Miller’s ‘magical’ number 7 +/- 2 items) that come from the sensory register and are ready to be processed through attention and recognition.[1] On the other side, information collected in the LTM storage consist of memories for the performance of actions or skills (i.e., procedural memories, “knowing how”) and memories of facts, rules, concepts, and events (i.e., declarative memories, “knowing that”). Declarative memory includes semantic and episodic memory. The former concerns broad knowledge of facts, rules, concepts, and propositions ('general knowledge'), the latter is related to personal and experienced events and the contexts in which they occurred ('personal recollection').

Although STM is closely related to the concept of ‘working memory’ (WM), STM and WM represent two distinct entities. STM, indeed, is a set of storage systems whereas WM indicates the cognitive operations and executive functions associated with the organization and manipulation of stored information.[2] Nevertheless, one hears the terms STM and WM often used interchangeably.

Furthermore, one must distinguish STM from the ‘sensory memory’ (SM) such as the acoustical echoic and iconic visual memories which are shorter in duration (fraction of a second) than STM and reflect the original sensation, or perception, of the stimulus. In other words, SM is specific to the stimulus' modality of presentation. This ‘raw’ sensory information undergoes processing, and when it becomes STM gets expressed in a format different from that perceived initially.

The famous Atkinson and Shiffrin model (or multi-store model), proposed in the late 1960s, explains the functional correlations between STM, LTM, SM, and WM.[3] Later on, a considerable number of studies demonstrated the anatomical and functional distinction between memory processes as well as neural correlates and functioning of STM and LTM subsystems. In light of these findings, several memory models have been postulated.[4][5] While certain authors suggested the existence of a single memory system encompassing both short- and long-term storage,[6] after 50 years the Atkinson and Shiffrin model remains a valid approach for an explanation of the memory dynamics. In light of more recent research, however, the model has several problems mostly concerning the characteristics of STM, the relationship between STM and WM as well as the transition from STM to LTM. 

Short-term memory: meaning and system(s)

It is a storage system that includes several subsystems with limited capacity. Rather than being a limitation, this restriction is an evolutionary survival advantage, since it allows paying attention to limited but essential information, excluding confounding factors. It is the classic example of the prey that must focus on the hostile environment to recognize a possible attack by the predator. Given the functional peculiarities of the STM (collection of sensorial information), the subsystems are closely related to the modalities of sensory memory. As a consequence, there have been several sensorial-associated subsystems postulated, including the visuospatial, phonological (auditory-verbal), tactile, and olfactory domains. These subsystems involve different patterns and functional interconnections with the corresponding cortical and subcortical areas and centers. 

The concept of working memory

In 1974, Baddeley and Hitch developed an alternative model of STM which they termed as working memory.[7] Indeed, the WM model does not exclude the modal model but enriches its contents. On the other side, the short-term store can be used to characterize the functioning of the WM. WM refers more to the entire theoretical framework of the structures and processes used for the storage and temporary manipulation of information, of which STM is only a component. In other words, STM is a functional storage element, while WM is a set of processes that also involve storage phases. WM It is the memory that we constantly use, which is always "online" when we have to understand something or solve a problem or make an argument, the cognitive strategies for achieving short term goals. The proof of the importance of this sort of 'operating system' of memory shows by the evidence that WM deficits are associated with several developmental disorders of learning, including attention-deficit hyperactivity disorder (ADHD), dyslexia, and specific language impairment (SLI).[8]

Short-term and Long-term memory

These types of memory can be classically distinguished based on storage capacity and duration. The capacity of the STM, indeed, has limitations in the amount and duration of information it can maintain. In contrast, LTM features a seemingly unlimited capacity that can last years. The functional distinctions between systems of memory storing and the exact mechanisms for how memories transfer from ST to LTM remain a controversial issue. Do STM and LTM represent one or more systems with specific subsystems? Although the STM probably represents a sub-structure of the LTM, which is a sort of long-term activated storage, rather than looking for a 'physical' division, it seems appropriate to verify the mechanisms of transition from a memory that is only a passage to a lasting memory. Although the classic multi-modal model proposed that storage of ST memories occurs automatically without manipulation, the matter seems to be more involved. The phenomenon concerns quantitative (number of memories) and qualitative (quality of memory) features.

Regarding quantitative data, although the number of Miller of 7 +/- 2 items identifies the number of elements included among individual slots, the grouping of memory bits into larger chunks (chunking) could allow storing a lot more information of bigger size and continuing to keep the magic number. The qualitative issue, or memory modulation within processing, is a fascinating phenomenon. It seems that the elements of STM undergo processing, which provides a sort of editing that involves the fragmentation of each element (chunking) and its re-elaboration and re-elaboration. This phase of memory processing is called encoding and can condition subsequent processing, including storage, and retrieval. The encoding process encompasses automatic (without conscious awareness) and effortful processing (through attention, practice, and thought) and allows us to retrieve information to be used to make decisions, answer questions, and so on. There are three pathways followed during the encoding step: the visual (information represented as a picture), acoustic (information represented as a sound), and semantic encoding (the meaning of the information). The processes interconnect with each other, so that information is broken down into different components. During recovery, the pathway that has produced the coding facilitates the recovery of the other components through a singular chain reaction. A particular perfume, for instance, makes us recall a specific episode or image. Of note, the encoding process affects the recovery, but the recovery itself undergoes a series of potential changes that can alter the initial content.

In neurofunctional terms, the difference between STM and LTM is the occurrence, in the LTM, of a series of events that must fix the engram(s) definitively. This effect occurs through the establishment of neural networks and expresses as neurofunctional phenomena including the long term potentiation (LTP) which is an increase in the strength of the neural transmission deriving from the strengthening of synaptic connections. This process requires gene expression and the synthesis of new proteins and is related to long-lasting structural alterations in the synapses (synaptic consolidation) of the brain areas involved such as the hippocampus is the case of declarative memories.

The role of the hippocampal network

Of note, the hippocampal neurogenesis regulates the maintenance of LTP.[9] However, the hippocampal network, including the parahippocampal gyrus, hippocampus, and neocortical areas is not the place where memories are stored, but it has a crucial role in forming new memories and in their subsequent reactivation. It seems that the hippocampus has a limited capacity and acquires information quickly and automatically without keeping it for long. Over time, the originally available information becomes permanent in other brain structures (in the cortex), independently from the activity of the hippocampus itself. The crucial mechanism of this transfer is the reactivation ("replay") of the configurations of neural activity. In other words, the hippocampus and the medial temporal structures connected to it are crucial for holding an event as a whole as it distributes in an organized way memory traces. It is an operating system that through different software can store, organize, process, and recover hardware files. This hippocampal-guided reactivation (retrieval) leads to the creation of direct connections between the cortical traces and then to the formation of an integrated representation in the neocortex including the visual association cortex for visual memory, the temporal cortex for auditory memory, and the left lateral temporal cortex for knowledge of word meaning. Moreover, the hippocampus has other specific tasks, for example, in the spatial memory organization.

Other brain areas are involved in memory processes; for example, the learning of motor skills has links to the activation of the cerebellar regions and brainstem nuclei. Furthermore, learning of perceptive activities (improvements in the processing of perceptive stimuli essential in everyday life activities such as understand spoken and written language)  involves, basal ganglia and sensory and associative cortices whereas learning cognitive skills (related to problem-solving) involve the medial temporal lobes initially.

Etiology

Different clinical conditions including, strokes, brain aneurysms, traumatic brain injuries, primitive or metastatic neoplasms, and infectious diseases (e.g., encephalitismay impair various components of STM. However, the damage to the STM is seldom selective. For example, aneurysm rupture can lead to STM loss, as well as LTM loss. Apart from diseases which induce STM alterations through direct neural damage, a wide range of medical conditions such as systemic infections, thyroid diseases, surgery (e.g., neuroinflammation-mediated postoperative delirium and postoperative cognitive dysfunction,[10] or psychiatric diseases (e.g., depression) or psychological (e.g., psychological trauma) can also impact STM. In this regard, pieces of evidence demonstrated that violence exposure during childhood impairs cognitive processes, including memory (psychogenic amnesia).[11] Cancer treatments, including radiation and chemotherapy, can induce STM damage through a complex neuroinflammation mechanism.[12]

Neurodegenerative conditions are paramount causes of memory impairment. For instance, one of the first signs of dementia is STM loss. In particular, memory loss (without interference in daily life or independent function) is the main feature of mild cognitive impairment (MCI) which represents the stage between the expected cognitive decline of normal aging and the more severe decline observed in Alzheimer disease (AD). Moreover, alterations in different memory domains have been shown in Parkinson disease (PD),[13] in those affected by Huntington disease (HD),[14] and in primary progressive aphasia (PPA).[15]

Other conditions that can impair memory tasks are alcohol and drug abuse (e.g., marijuana), heavy cigarette smoking, sleep deprivation, severe stress, and vitamin B12 deficiency. Prolonged high alcohol intake can lead to Korsakoff syndrome, which is a complex amnestic disorder with neuropsychological sequelae caused by vitamin B1 (thiamine) deficiency. In addition to alcohol, other causes can lead to vitamin B1 deficiency (non-alcoholic Korsakoff syndrome) with related memory disorders, including dietary deficiencies, prolonged vomiting, and eating disorders. Again, Korsakoff-like amnestic syndromes have also presented after brain lesions involving anteromedian thalamus and hippocampus.[16]

Among other causes of memory impairment, a common side effect of electroconvulsive therapy (ECT) is STM alteration during treatment. A special issue concerns medications-induced memory loss. The list of drugs implicated includes benzodiazepines (BDZs), antiepileptic drugs,[17] opioids,[18] tricyclic antidepressants.[19] Concerning statin use and memory loss, there is weak evidence (observational data, including case reports).[20] Most of these drugs (e.g., benzodiazepines) act by impairing memory processing and, in turn, can present an obstacle to the consolidation of information.[21]

Epidemiology

Epidemiological data are related to the different conditions which induce memory impairment. For instance, concerning neurodegenerative diseases, about 15 to 20 % of people aged 65 or older have mild cognitive impairment; of this, approximately one-third develop AD within 5 years’ follow-up.[22] Furthermore, the existing cases of AD (prevalence) are of 5.8 million Americans (2018), and estimates are that the annual number of new cases (incidence) of all dementias will double by 2050.[23] Again, PD affects approximately 1% of the population above 60 years, whereas the incidence of Huntington disease is of 0.38 per 100000 per year.[24][25] For non-neurodegenerative conditions, it is difficult to make an epidemiological estimate as the decline of memory is not always in the clinical picture. 

Pathophysiology

The amnestic syndrome

Amnestic syndrome is an impairment in the ability to form new memories. Regardless of etiology, it seems that memories of recent events (STM) are most vulnerable, whereas older memories (LTM) are more 'resilient' and protected from damage. This concept is not new, as, towards the end of the nineteenth century, the French psychologist Theodule-Armand Ribot (1839-1916) demonstrated that amnesia affects memories in reverse order of their development.[26] This idea is why a substantial distinction is necessary between anterograde amnesia and retrograde amnesia. The former concerns the new memories and the latter what is well established by neural networks, which is why some conditions (e.g., drugs such as BDZs) can lead to a deficit, especially within the STM. In turn, amnestic disorders primarily affect anterograde memories. 

Neural correlates for STM domains and damages.

Research proved that lesions to the prefrontal cortex in primates caused STM alterations. Based on the brain area affected by the damage, research has demonstrated specific modifications in the different domains of STM. The assumption is that these different components are the expression of different neuronal correlates. In this regard, neuroimaging studies reported significant information. For instance, inferior parietal lobule, frontal premotor regions, and insula in the dominant hemisphere are the major neural correlates of the phonological STM subtype.[27] In particular, depending on the type of function, the cerebral areas appointed to the phonological aspects of the verbal STM are the inferior parietal cortex left for the phonological warehouse and the Broca area for articulatory revision. Again neuroimaging investigations proved that the neural correlates of spatial STM memory involve the occipital extrastriate, posterior parietal, dorsolateral premotor, and prefrontal cortices.[28] Yet, fRMI studies highlighted the importance of the area dorsal frontal (ocular fields, Brodmann area 8) for retaining oculomotor information, and the intraparietal sulcus responsible for retaining the space positions.

On the other side, the medial temporal lobes play a fundamental role in the coding and consolidation of the type of memories that are accessible to consciousness, but these regions do not permanently preserve memories and are not necessary for encoding or consolidating other types of memory. The demonstration comes from the emblematic case of patient H.M. who, suffering from severe posttraumatic epilepsy, was operated on median resection of the temporal lobe bilaterally.[29] A serious picture of amnesia emerged in which the older memories (e.,g. childhood) had remained almost intact, but the subject showed difficulty in recovering memories acquired in the 3 years before the operation, especially for personal events (retrograde amnesia). Above all, he demonstrated a severe incapacity to store new information (anterograde amnesia) although the STM was not impaired. In other cases, however, patients showed deficits in WM despite LTM preserved. For example, although the patient K.M. had difficulty in immediately recalling lists of 4 words, he was also faster and better than normal subjects to learn long lists of words.[30] In this latter case, the damage had localized in the left temporoparietal regions (perisylvian area).

Relationship between STM and LTM: clinical evidence.

Because STM and LTM are distinct memories with distinct mechanisms, a selective deterioration of STM may not impair the tasks of LTM. However, it is also true that difficulties in STM performances can trigger a pathogenetic chain that involves other types of memory. Probably, the interconnections between STM and LTM require more explanation.[31] Several clinical pieces of evidence prove a mechanistic relationship between the two systems. For instance, deficits in verbal STM are commonly recognized in children with reading difficulties and are associated with learning disorders featuring impairment in reading. Similarly, in its early stages (i.e., mild cognitive impairment), Alzheimer disease typically affects STM but not LTM, which becomes progressively altered as the disease progresses.

History and Physical

The impairment of STM involves forgetting information to which the subject has been recently exposed. An individual with signs of losing STM, indeed, asks for the same questions repeatedly, forgets where he just put something, forgets recent events or something he saw or read recently. The loss of immediate memory is also termed as fixation amnesia. The clinical features of STM impairment, however, are variable and depend on the underlying cause for the memory alteration. Within the STM, different memory domains such as verbal or visuospatial components, and in different degrees, can be altered. In most cases, the memory alterations are blurred and last as long as the pathology that caused them, or resolves over weeks or months (e.g., postoperative cognitive dysfunction).

In neurodegenerative diseases such as dementia, the decline of STM is generally progressive, involving different domains and, in turn, other memory systems. On the other side, memory loss in mild cognitive impairment can remain unaltered, worsen, or improve. In about 30% of brain aneurysm cases, STM/LTM problems disappear over time, although recovery may take weeks. In most cases (e.g., psychogenic amnesia) memories can be recovered for instance through psychological interventions (recover of undeleted files); nevertheless, if amnesia has lasted a long time such as months or years, the recovery is not possible (deleted files), and the subject projects into a new life (the fugue state).

Memory impairment can be part of complex clinical pictures. For example, alcohol-induced Korsakoff syndrome characteristically demonstrates STM/LTM memory impairment (anterograde, retrograde), confabulation (invented memories used to fill memory gaps and blackouts) and psychiatric symptoms. Neurological manifestations associated with thiamine deficiency (Wernicke encephalopathy) can accompany Korsakoff syndrome, and the combination is termed as Wernicke-Korsakoff syndrome. 

Evaluation

Different approaches can be useful for evaluating STM domains. For instance, the verbal component investigation is through simple tests based on the recall of words, or digits. The simple span tasks approach, also known as STM tasks, examines the storage of either verbal (phonological) or visuospatial information. Alternatively, more complex methods such as those based on serial position effects in the immediate serial recall are options. Population-specific approaches are used, for example, in children. In this setting, the performances of the STM are investigated, within the WM, through the Automated Working Memory Assessment,[32] and the Working Memory Test Battery for Children.[33]

Memory evaluation and cognitive decline

Although memory gets investigated among cognitive performances by validated instruments such as the mini-mental state examination (MMSE) and the Montreal Cognitive Assessment (MoCA), research has led to the design of specific tools for assessing STM impairment alone and provide information about the degree of the memory impairment. The Short-Term Memory Recall Test and its simplified version can be useful for identifying memory impairment as a pre-dementia state,[34] whereas the Temple Assessment of Language and Short-term Memory in Aphasia (TALSA) is a tool for investigating STM impairment in post-stroke aphasia. Other tools can help in evaluating memory alterations in different clinical conditions of progressive cognitive decline. For instance, the California Verbal Learning Test-3 (CVLT-3) is useful for distinguishing memory disorders of AD from Huntington disease.[35] Further diagnostic examinations must focus on the cause of memory decline. In this regard, it may be necessary to carry out instrumental investigations (e.g., MRI or CT scan) or laboratory examinations (e.g., vitamin B12).

Treatment / Management

There have been several proposed behavioral and non-behavioral strategies for enhancing memory tasks. Behavioral approaches, or cognitive training, are mostly focused on the maintenance rehearsal which facilitates the memory processing through repetitive stimuli, and the elaborative rehearsal which focuses on the association of new information with already stored knowledge and analysis of new information to make it memorable. There are several proposed behavioral strategies, and some of these, such as the combination of Tai Chi movements and breathing,[36] are particularly interesting. However, further research and controlled studies need to confirm their real benefit. Concerning pharmacological approaches, although commonly prescribed, drugs approved to manage memory symptoms of AD such as cholinesterase inhibitors have not demonstrated significant benefits in slowing-down or preventing the progression of mild cognitive impairment to AD.[37][38]

Apart from the complex strategies used in specific settings and when the deficit appears to be very clear, involving different domains and other types of memory, it is possible to train the STM using simple expedients. One of these is at the base of the nursery rhymes used to let children memorize numbers, months of the year, etc. This strategy works by attaching a word, phrase or image to an object. In practice, it is the same process that we put into practice when we choose a password. Memory games, which consist of the short exposure of objects (e.g., pictures of animals) to then remember and associate them, is another system that can work to exercise memory.

Ongoing investigations

On these bases, researchers have designed more complex training programs for specific contexts. These non-pharmacological approaches are essential in the case of neurodegenerative conditions when there are no effective therapies and in those in which the impairment is not severe and can be still slowed down or (probably) stopped. For example, in mild cognitive impairment – for which no medications currently have approval by the U.S. Food and Drug Administration (FDA) – computer-based memory training programs are adopted. The computer brain fitness training can also combine with wellness education programs and physical exercise (yoga). Web-based cognitive training (30 internet sessions, 4 to 5 times a week) may be useful alterations involving memory processing in Parkinson disease.

Apart from cognitive training, non-behavioral strategies concern the use of transcranial direct current stimulation in STM impairment due to primary progressive aphasia whereas there are ongoing investigations on the effect of nutraceuticals such as thymoquinone or green tea against AD-related STM decline, and tryptophan-tyrosine (WY)-related peptides (lactolin) in stress-induced memory alterations.[39][40][41] Although several studies have shown that Ginkgo biloba can improve the function of STM,[42] the scientific evidence in this direction is limited.

Enhancing Healthcare Team Outcomes

In most cases, the management of problems related to alterations of the STM requires an interdisciplinary approach. The target is to design a patient-centered treatment through the involvement of several health professionals. Many clinical conditions associated with memory disorders have very complex clinical pictures requiring a care response aimed at improving several outcomes, including cognition, functioning, mood, and, in turn, quality of life. The team must consist of professional figures able to: 1) perform a careful neuropsychological assessment; 2) collect information to make different diagnoses; 3) select the appropriate strategy (behavioral/non-behavioral); 4) manage communication for improving patient compliance and treatment adherence; 5) support patient and family; 6) adopt the more appropriate psychological strategy (e.g., group cognitive-behavioral therapy) 6) perform behavioral programs focused on wellness education (e.g., sleep hygiene); 7) manage pharmacological approaches; 8) design programs of physical activity; 9) evaluate outcomes.

Specialty-trained psychological nurses can be of great assistance to the physicians in these cases. They will take basic histories, verify medication compliance, and monitor for overall treatment effectiveness before the clinicians investigate the patient's status or change of status. While early STM impairment does not fall into pharmaceutical therapy, as the decline continues and concerns about Alzheimer disease or Parkinson disease appear, the pharmacist will assume a much more significant role, including agent and dose verification, medication reconciliation, and working directly with the nursing and physician staff to optimize therapy and minimize adverse effects. This type of interprofessional team approach is necessary for optimal patient results in managing STM impairment. [Level V]


References

[1] Cowan N, George Miller's magical number of immediate memory in retrospect: Observations on the faltering progression of science. Psychological review. 2015 Jul     [PubMed PMID: 25751370]
[2] Miller EK,Lundqvist M,Bastos AM, Working Memory 2.0. Neuron. 2018 Oct 24     [PubMed PMID: 30359609]
[3] Atkinson RC,Shiffrin RM, The control of short-term memory. Scientific American. 1971 Aug     [PubMed PMID: 5089457]
[4] Baddeley AD,Hitch GJ, Development of working memory: should the Pascual-Leone and the Baddeley and Hitch models be merged? Journal of experimental child psychology. 2000 Oct     [PubMed PMID: 11017721]
[5] Madl T,Franklin S,Chen K,Trappl R,Montaldi D, Exploring the Structure of Spatial Representations. PloS one. 2016     [PubMed PMID: 27347681]
[6] Saint-Aubin J,Poirier M, Word frequency effects in immediate serial recall: item familiarity and item co-occurrence have the same effect. Memory (Hove, England). 2005 Apr-May     [PubMed PMID: 15948617]
[7]     [PubMed PMID: 30478520]
[8]     [PubMed PMID: 21189804]
[9]     [PubMed PMID: 29986876]
[10]     [PubMed PMID: 28984099]
[11]     [PubMed PMID: 29144224]
[12]     [PubMed PMID: 30565571]
[13]     [PubMed PMID: 24615718]
[14]     [PubMed PMID: 28482181]
[15]     [PubMed PMID: 26039844]
[16]     [PubMed PMID: 17416834]
[17] Barton S,Nadebaum C,Anderson VA,Vajda F,Reutens DC,Wood AG, Memory dysfunction in school-aged children exposed prenatally to antiepileptic drugs. Neuropsychology. 2018 Oct     [PubMed PMID: 29975072]
[18] Kamboj SK,Tookman A,Jones L,Curran HV, The effects of immediate-release morphine on cognitive functioning in patients receiving chronic opioid therapy in palliative care. Pain. 2005 Oct     [PubMed PMID: 16198201]
[19] Eizadi-Mood N,Akouchekian S,Yaraghi A,Hakamian M,Soltani R,Sabzghabaee AM, Memory Impairment following Acute Tricyclic Antidepressants Overdose. Depression research and treatment. 2015     [PubMed PMID: 25649497]
[20]     [PubMed PMID: 26704648]
[21]     [PubMed PMID: 25844143]
[22]     [PubMed PMID: 24174927]
[23]     [PubMed PMID: 31374073]
[24]     [PubMed PMID: 22692795]
[25]     [PubMed PMID: 31356286]
[26]     [PubMed PMID: 29589321]
[27]     [PubMed PMID: 21049325]
[28]     [PubMed PMID: 18603299]
[29] Augustinack JC,van der Kouwe AJ,Salat DH,Benner T,Stevens AA,Annese J,Fischl B,Frosch MP,Corkin S, H.M.'s contributions to neuroscience: a review and autopsy studies. Hippocampus. 2014 Nov     [PubMed PMID: 25154857]
[30] Paulesu E,Shallice T,Danelli L,Sberna M,Frackowiak RSJ,Frith CD, Anatomical Modularity of Verbal Working Memory? Functional Anatomical Evidence from a Famous Patient with Short-Term Memory Deficits. Frontiers in human neuroscience. 2017     [PubMed PMID: 28567009]
[31] Norris D, Short-term memory and long-term memory are still different. Psychological bulletin. 2017 Sep     [PubMed PMID: 28530428]
[32]     [PubMed PMID: 17654276]
[33]     [PubMed PMID: 18241387]
[34]     [PubMed PMID: 20215857]
[35]     [PubMed PMID: 31060638]
[36]     [PubMed PMID: 31190769]
[37]     [PubMed PMID: 30651152]
[38]     [PubMed PMID: 30633043]
[39]     [PubMed PMID: 29479315]
[40]     [PubMed PMID: 28642806]
[41]     [PubMed PMID: 31068787]
[42]     [PubMed PMID: 27069717]