Amnesic Syndrome In Handbook of Human Memory Foundations and Applications Stroke

III.1. Stroke A stroke occurs when a blood vessel that carries energy supplies to the brain is either occluded (ischemic) or ruptures (hemorrhagic). Ischemic strokes lead to cell death within minutes due to deprivation of oxygen and nutrients. Hemorrhagic strokes cause cell damage through swelling, pressure, and toxicity, related to the collection of blood in brain tissues. Because a stroke can occur in a wide variety of locations, it constitutes the only etiology that can affect the entire memory circuitry, and its study has been helpful for identifying the points of convergence of the network (for review, see Lim & Alexander, 2009). III.1.1. Medial Temporal Lobe Lesions Bilateral posterior cerebral artery (PCA) infarction is a well-documented cause of amnesia (Benson, Marsden, & Meadows, 1974; Victor, Angevine, Mancall, & Fisher, 1961). The PCA represents a main source of blood supply for the MTL, especially perfusing posterior and inferior areas, including the posterior hippocampus and parahippocampal gyrus. The PCA territory is susceptible to bilateral infarction as both left and right arteries arise from one common (basilar) artery. Memory deficits resulting from bilateral PCA infarction are consistent with a classic amnesic syndrome, including prominent anterograde amnesia, variable retrograde amnesia extending to many years prior to the stroke, and relatively preserved working memory and intelligence (Benson et al., 1974; Schnider, Regard, & Landis, 1994; Victor et al., 1961). Unilateral left PCA infarction can yield a transient amnesic syndrome, lasting a few weeks to a year, with long-term residual memory deficits restricted to the verbal domain (De Renzi, Zambolin, & Crisi, 1987; Ott & Saver, 1993; Von Cramon, Hebel, & Schuri, 1988). Right PCA infarction does not tend to produce full blown amnesia (Von Cramon et al., 1988), but deficits have been reported in visual and spatial memory, for example involving learning the location of objects (Luzzi, Pucci, Di Bella, & Piccirilli, 2000). This functional lateralization is consistent with findings from neuroimaging studies and unilateral temporal lobectomy patients, demonstrating relative specialization of the left hippocampus for verbal memory (Frisk & Milner, 1990; Powell et al., 2005), and right hippocampus for visuospatial memory (Burgess, Maguire, & O’Keefe, 2002; Smith & Milner, 1981). The PCA territory supplies a large area of the temporal lobe, and a number of cognitive and perceptual deficits may accompany amnesia secondary to PCA infarction, including visual field defects, alexia, anomia, color agnosia, constructional apraxia, topographical disorientation, prosopagnosia, and cortical blindness (Benson et al., 1974). These associated perceptual and language deficits can complicate assessment of verbal and visuospatial memory abilities. The anterior and superior portions of the MTL, including the anterior hippocampus and amygdala, are supplied by the anterior choroidal artery (AchA), which originates 2-5 mm distal to the posterior communicating artery. The AchA may be subject to infarction but also to bleed by ruptured aneurysm or traumatic tearing (Yu, Xu, Zhao, & Yu, 2018). Amnesia resulting from isolated stroke of the AchA territory has been reported in a handful of patients (Amarenco et al., 1988; Ott & Saver, 1993). III.1.2. Thalamic Lesions Significant memory difficulties have been associated with strokes to the medial and anterior portions of the thalamus (Gold & Squire, 2006; Graff-Radford, Tranel, Van Hoesen, & Brandt, 1990; Von Cramon et al., 1985), regions that are supplied by a complex network of small arteries, including the tuberothalamic, paramedian, and anterior choroidal arteries. The structure of these vascular connections tends to vary widely across individuals (Schmahmann, 2003). This variability, added to a tight packing of numerous nuclei in a small space, has rendered difficult identifying the contribution of specific nuclei to memory functions. Further, because the thalamus acts as a relay for perceptual and frontal processing, a complex array of cognitive deficits often associated with thalamic strokes may contribute to decreased memory performance. These include attention and executive dysfunction (Carlesimo, Lombardi, & Caltagirone, 2011; Van der Werf, Witter, Uylings, & Jolles, 2000), transcortical aphasia, hemispatial neglect, and visuospatial processing difficulties (Bogousslavsky, Regli, & Assal, 1986). The memory disturbances resulting from thalamic stroke have traditionally been classified together under the term “diencephalic amnesia”, implying a consistent constellation of symptoms. Recent reviews, however, have highlighted the need to better distinguish between thalamic lesions that cause an amnesic syndrome and those that cause memory deficits related to executive dysfunction (Carlesimo et al., 2011; Van der Werf et al., 2000). An amnesic syndrome similar to that resulting from hippocampal lesions occurs in the context of rostral thalamic strokes that damage the anterior thalamic nuclei or the mammillary-thalamic tract, which connects the hippocampus to the anterior thalamic nuclei. By contrast, milder memory disturbances associated with executive dysfunction occur with damage to other thalamic areas, including the medial dorsal nucleus, midline nuclei, and intralaminar nuclei (Danet et al., 2015; Van der Werf et al., 2003). Damage to the dorsomedial thalamic nuclei has also been associated with impaired familiarity-based processes (reviewed in Carlesimo et al., 2011). These findings are consistent with two proposed independent MTL-thalamic circuits, one subserving recollection through connections between the hippocampus, mammillary bodies, and anterior thalamic nucleus, and the other subserving familiarity through perirhinal cortexmedial dorsal thalamus nucleus connections (Aggleton & Brown, 1999; but see Cipolotti et al., 2008). III.1.3. Basal Forebrain Lesions The most common vascular etiology of basal forebrain lesions is ruptured aneurysm of the anterior communicating artery (ACoA). In particular, lesions of the septal nuclei and diagonal band of Broca – the main sources of cholinergic projections to the hippocampus – have been associated with severe memory impairment (Alexander & Freedman, 1984; Damasio et al., 1985). Additional disruption of frontal-subcortical networks is often observed due to hemorrhage-induced swelling, pressure, and blood toxicity. In the acute phase after surgical repair of the aneurysm, patients typically present with a severe confusional state, followed by apathy, confabulation, and denial of illness (Alexander & Freedman, 1984). Over the weeks to months that follow, confusion tends to clear, but memory impairments, colored by the presence of executive disturbance, become apparent. These impairments include inefficient learning (Diamond, DeLuca, & Kelley, 1997), disproportionate deficits in recall (Hanley, Davies, Downes, & Mayes, 1994; Volpe & Hirst, 1983) and contextual memory (Damasio et al., 1985; Parkin, Leng, Stanhope, & Smith, 1988), as well as retrograde amnesia that is generally less severe than in MTL lesions (O’Connor & Lafleche, 2004). These impairments all tend to improve in parallel with recovery of executive functioning (D’Esposito, Alexander, Fischer, McGlinchey-Berroth, & O’Connor, 1996). Also closely linked to executive function is confabulation, which involves statements or actions that reflect unintentional distortions of memory (Gilboa & Verfaellie, 2010). Confabulations can range from intrusions of past experiences (“I am at the hospital for hip replacement surgery”) to completely fantastical statements (“I am at the hospital because I am serving meals to patients”) (Stuss, Alexander, Lieberman, & Levine, 1978). III.1.4. Retrosplenial Lesions Lesions restricted to the retrosplenial cortex, albeit rare, may occur following ischemic or hemorrhagic stroke in the region of the splenium of the corpus callosum (for review, see Maguire, 2001). Consistent with disruption of the extended hippocampal circuit, retrosplenial damage can produce a classic amnesic syndrome (Valenstein et al., 1987; Vann, Aggleton, & Maguire, 2009). Deficits in spatial navigation affecting both new and familiar environments are a hallmark impairment of retrosplenial damage. The restrosplenial cortex is thought to play an important role in memory by integrating various spatial perspectives (for review, see Mitchell, Czajkowski, Zhang, Jeffery, & Nelson, 2018), allowing translation between allocentric (or viewpoint-independent) representations mediated by the MTL and egocentric (or viewpoint-dependent) representations mediated by the parietal cortex (Burgess, 2008). In line with this notion, retrosplenial cortex is engaged when information from the visual environment needs to be retrieved from memory to orient oneself in space (see chapter 3.3. “Memory for Space”). This may also explain its role in the retrieval of autobiographical memories, as such memories similarly require referencing oneself within a spatial context and updating of spatial representations as events are recalled. Whereas a full amnesic syndrome typically occurs following bilateral or unilateral left lesions, spatial disorientation is the primary symptom associated with unilateral right lesions (Maguire, 2001). III.2. Hypoxic-Ischemic Brain Injury Hypoxic-ischemic brain injury results from shortage of oxygen and nutrients to the brain, due to hypoxia (deprivation from oxygen), ischemia (decreased blood perfusion), cytotoxicity (blocked binding of oxygen to hemoglobin), or their combination (Busl & Greer, 2010). The most common causes of hypoxic-ischemic brain injury are cardiac arrest, respiratory failure, incomplete suffocation (e.g., near-drowning, nearhanging), and carbon monoxide poisoning. Cell damage, in this context, results from a cascade of biochemical events, including influx of calcium into the cells, edema, release of excitatory neurotransmitters, excitotoxicity, and the formation of unstable free oxygen radicals. Brain structures particularly vulnerable to hypoxic-ischemic injury are those with high metabolic demands, such as the hippocampus, cerebellum, and basal ganglia, as well as gray and white matter located at the fringes of arterial perfusion territories (Busl & Greer, 2010). Upon initial presentation, hypoxic-ischemic brain injury may involve disorders of consciousness (coma, vegetative state), seizures, motor disturbances, and a variable range of cognitive and behavioral changes (Anderson & Arciniegas, 2010). Following a period of recovery, some patients are left with severe memory deficits. One of the first well-documented cases of isolated amnesia following hypoxicischemic injury is that of R.B., a 52-year-old male patient who developed amnesia following heart surgery complication and subsequent ischemic event (Zola-Morgan et al., 1986). R.B. presented with moderate anterograde amnesia for verbal and non-verbal material in the context of very mild retrograde amnesia and otherwise intact cognitive abilities. Post-mortem histological examination revealed bilateral lesions restricted to the CA1 subfield of the hippocampus. A subsequent autopsy study of three cases confirmed that circumscribed CA1 lesions are sufficient to produce anterograde amnesia (Rempel- Clower et al., 1996). Extensive temporally graded retrograde amnesia spanning 15 years or more was also reported in this study, with severity of both anterograde and retrograde deficits correlated with hippocampal lesion size, extending beyond CA1. Severe anterograde and retrograde amnesia were also seen in a 67-year-old retired seaman who had suffered repeated ischemic events accompanied by seizures, with bilateral damage restricted to the CA1 and CA2 subfields of the hippocampus (Kartsounis, Rudge, & Stevens, 1995). In that case, retrograde amnesia extended several decades without suggestion of a clear temporal gradient. Hippocampal amnesia has traditionally been regarded as the prototypical presentation of hypoxic-ischemic injury, possibly because of the focus in the literature on anoxic patients with restricted hippocampal damage. Yet, this presentation is rare. Focal hippocampal damage occurs primarily in the context of slow or stepwise hypoxic (e.g., carbon monoxide) or excitotoxic (e.g., seizures) injury, but more extensive damage is the norm following sudden, global, and complete shortage of oxygen, such as in cardiac arrest (Lim, Alexander, LaFleche, Schnyer, & Verfaellie, 2004; Markowitsch, WeberLuxemburger, Ewald, Kessler, & Heiss, 1997). The basal ganglia, thalamus, and watershed areas of neocortex tend to be damaged more frequently than the hippocampus, leading to executive dysfunction, changes in behavior or personality (e.g., emotional lability, irritability, apathy, or child-like behaviors), and visuoperceptual deficits (Caine & Watson, 2000), as well as subtle motor difficulties (Lim et al., 2004). In studies examining the cognitive consequences of cardiac arrest in clinical settings, patients almost always display a dysexecutive syndrome, whereas about half also demonstrate severe memory impairments (Lim et al., 2004; Peskine, Picq, & Pradat-Diehl, 2004). Developmental Amnesia. Hypoxic-ischemic episodes during the neonatal period are the primary etiology of developmental amnesia. Patients with developmental amnesia achieve normal developmental milestones, including language and vocabulary acquisition, and attain average intellectual abilities, but show severely compromised development of episodic memory (Elward & Vargha-Khadem, 2018). The episodic memory impairment is characterized by markedly impaired recall and relatively spared recognition (Adlam, Malloy, Mishkin, & Vargha-Khadem, 2009), consistent with preservation of familiarity (Bindschaedler, Peter-Favre, Maeder, Hirsbrunner, & Clarke, 2011; Brandt, Gardiner, Vargha-Khadem, Baddeley, & Mishkin, 2009). As described earlier, especially striking in these patients is the impressive capacity for acquiring semantic knowledge, but subtle impairment in the structure of semantic knowledge may be present (Blumenthal et al., 2017). The pattern of memory impairment seen in developmental amnesia was initially attributed to selective lesions in the hippocampus (Vargha-Khadem et al., 1997), although additional abnormalities in the putamen, thalamus and retrosplenial cortex were also observed (Vargha-Khadem et al., 2003). More recent evidence has revealed that other parts of the extended hippocampal system, in particular the mammillary bodies and anterior thalamus, are also commonly involved (Dzieciol et al., 2017). Notably, abnormal prenatal development of the extended hippocampal system with complete absence of mammillary bodies has recently been described as a possibly distinct origin of developmental amnesia (Rosenbaum et al., 2014). Compared to adult-onset amnesia, patients with developmental amnesia can be quite high functioning, relying on their semantic memory to keep up with their affairs, news items, and new discoveries (Elward & Vargha-Khadem, 2018). They also tend to produce reasonable responses to questions about specific episodes, thus giving the impression of intact memory (e.g., Brandt et al. 2006). For example, Elward & VarghaKhadem related the case of Jon, who had bilateral hippocampal atrophy following neonatal hypoxia-ischemia, and would visit their lab regularly. On one occasion, the elevator was broken, and Jon had to climb the equivalent of 14 floors of stairs. Upon questioning, Jon had forgotten the event and, relying on semantic memory, recounted taking the elevator as usual, “because [he] always does” (pp.23). III.3. Encephalitis Encephalitis is an inflammation of the brain parenchyma resulting in neurological dysfunction. Herpes simplex encephalitis and encephalitis secondary to autoimmune disease both can lead to dense amnesia. III.3.1. Herpes Simplex Encephalitis Brain infection by the herpes simplex virus is rare, but occurs when the virus, which tends to lay dormant in the trigeminal ganglia, is reactivated and transmitted to the brain (for review, see Bradshaw & Venkatesan, 2016). In the acute stage, patients may experience fever, rapid-onset headaches, lethargy, confusion, aphasia, seizures, focal neurological signs, and in some cases coma (Kennedy & Chaudhuri, 2002). Outcomes are poor in the absence of antiviral therapy, with mortality exceeding 70% and most survivors being left with disabling impairments. However, antiviral treatment has markedly improved these outcomes (Hokkanen & Launes, 2007). Neural damage following herpes simplex encephalopathy centers on the medial temporal lobes, but often extends to the anterolateral and inferior temporal cortices, orbitofrontal cortex, and insula (Colchester et al., 2001; Damasio & Van Hoesen, 1985; Kapur et al., 1994). Memory difficulties constitute the most commonly reported deficit, and because of the relative preservation of frontal brain regions, patients often display insight into their difficulties. Alterations in mood and personality, and difficulties with verbal semantic and visuoperceptual abilities, however, can also occur (Hokkanen et al., 1996). Anterograde amnesia in herpes simplex encephalitis can be profound, with the pattern of impairment depending on the extent of neural damage within and beyond the MTL. For example, patient S.S, who suffered a severe episode of herpes simplex encephalitis, initially presented with one-month coma, aphasia, and hemiparesis. Although his speech and motor problems resolved, he was left with a complete inability to remember events that occurred following his illness (Cermak & O’Connor, 1983). He also had a striking inability to acquire new semantic knowledge, despite repeated exposure through newspaper and television programs (Verfaellie et al., 2000). Contrasting with S.S., patient R.F.R. demonstrated acquisition of some new word meanings in a 16-year follow-up, as well as some, although more limited, knowledge of new celebrities (McCarthy, Kopelman, & Warrington, 2005). This variability might be attributed to the sparing of the left lateral temporal lobe in R.F.R compared to S.S., presumably allowing for direct, albeit inefficient, cortical learning of new semantic representations. With improved treatment, unilateral lesions are now more commonly reported (Chow et al., 2015). As expected, right temporal damage disproportionately affects nonverbal memory (Eslinger, Damasio, Damasio, & Butters, 1993) and left temporal damage disproportionately affects verbal memory (Tranel, Damasio, & Damasio, 2000). Retrograde amnesia is typically also very extensive (Cermak & O’Connor, 1983), with the pattern of deficits depending on laterality. Notably, disproportionate right lateralized damage has been associated with complete inability to recount any past personal events, including from childhood. Personal factual information (e.g., remembering the name of a first grade teacher) tends to be relatively better preserved, but with answers often stereotyped and unelaborated (McCarthy et al., 2005; O’Connor, Butters, Miliotis, Eslinger, & Cermak, 1992). By contrast, patients with disproportionate left lateralized damage, extending into the left anterior inferotemporal cortex, display impaired semantic memory (i.e., impaired knowledge of the name, meaning, and attributes of words and pictures) in the context of otherwise preserved language and perceptual abilities (De Renzi et al., 1987). In rare cases, category-specific impairments have been reported, for example with differential deficits for concrete versus abstract concepts or for animate versus inanimate objects (for review, see McKenna & Warrington, 2000). III.3.2. Autoimmune Encephalitis Autoimmune encephalitis is an inflammation of the brain caused by the development of antibodies by the immune system against proteins implicated in neurotransmission. This reaction may sometimes signal the presence of an underlying tumor in another part of the body (paraneoplastic encephalitis). In recent years, a number of studies have focused on the leucine-rich glioma inactivated (LGI1) antibody subtype as a cause of amnesia. This subtype is often categorized under the family of voltage-gated potassium channels (VGKCs)-complex antibodies (for review, see Leypoldt, Armangue, & Dalmau, 2015). In the acute phase, patients with anti-LGI1 encephalitis present with memory deficits, confusion, frequent seizures, and sleep disruption. Without timely and aggressive immunotherapy, patients may be left with lesions that selectively affect the hippocampus. One study suggested that the disease specifically targets the CA3 hippocampal subfield, with extent of CA3 atrophy predicting severity of episodic memory impairment (Miller et al., 2017), but another study reported damage also extending to other hippocampal subfields (Finke et al., 2017). Considering the homogeneity of lesions to the hippocampus, patients with anti-LGI1 may provide an important assay of hippocampal function. In a study assessing seven patients (Lad, Mullally, Houston, Kelly, & Griffiths, 2019), significant anterograde amnesia was reported for verbal and visual material, with recognition relatively preserved compared to recall, consistent with sparing of familiarity processes. Retrograde amnesia was significant for recall of episodic events, with half of the participants demonstrating equal impairment across all life periods, and the other half showing a temporally graded trend (also see Chan, Henley, Rossor, & Warrington, 2007). Personal semantic memory, by contrast, was intact across all time periods for all patients. The authors postulated that intact semantic knowledge of childhood might support early autobiographical memory in those patients who demonstrated an episodic memory temporal gradient. III.4. Korsakoff Syndrome Korsakoff syndrome is a chronic disorder subsequent to incomplete resolution of Wernicke’s encephalopathy, caused by thiamine deficiency (Arts, Walvoort, & Kessels, 2017; Kopelman, 1995). It is most commonly seen in individuals with a history of severe alcohol abuse, reflecting a combination of poor nutritional habits and malabsorption of thiamine in the intestine due to alcohol-induced damage of the intestinal tract. However, non-alcoholic etiologies associated with thiamine deficiency have also been described (Scalzo, Bowden, Ambrose, Whelan, & Cook, 2015). The acute phase of Wernicke encephalopathy is characterized by a confusional state, oculomotor problems, and ataxia (Caine, Halliday, Kril, & Harper, 1997). Prompt thiamine replacement therapy is critical to prevent the occurrence of fatal midbrain hemorrhages and leads to clearing of the confusional state. However, if treatment is delayed, patients may present with irreversible amnesia, marking the onset of the chronic Korsakoff stage of the syndrome. Persistent changes in personality, including apathy, flat affect, and decreased insight, are also common (Arts et al., 2017). The main pathology of Wernicke-Korsakoff syndrome consists of punctate lesions in the area of the aquaduct, third ventricle, and fourth ventricle, areas known to be especially sensitive to thiamine deficiency, often with concomitant frontal atrophy (Victor, Adams, & Collins, 1989). The exact neural substrate of the amnesia associated with Korsakoff syndrome has been a matter of much debate; lesions of the dorsomedial thalamic nuclei, anterior thalamic nuclei, and mammillary bodies each have been postulated to be critical (for review, see Kopelman, 2015). An autopsy study of the brains of individuals who had Wernicke encephalopathy in the context of alcohol dependence found that neuronal loss in the anterior thalamic nuclei differentiates Korsakoff patients from those without amnesia, whereas degeneration in the dorsomedial thalamus and mammillary bodies is common to both groups (Harding, Halliday, Caine, & Kril, 2000). The central symptom of Korsakoff syndrome is an inability to acquire new verbal and nonverbal information (Fama, Pitel, & Sullivan, 2012). Even in the face of extensive repetition, patients have difficulty learning new information and they forget information to which they were exposed just minutes before. Susceptibility to interference is a core feature of the amnesic presentation, and may reflect both failure to fully encode information and competition from irrelevant information at the time of retrieval (Verfaellie, 2003). Also characteristic are disproportionate impairments in contextual memory. Even when patients are provided additional exposure to boost their item memory, memory for the temporal sequence in which information is presented, and less consistently its spatial context, remains impaired (Kessels & Kopelman, 2012). It is likely that frontal executive deficits influence the amnesic presentation. Korsakoff patients also suffer from severe retrograde amnesia in a temporallygraded pattern, with memories of childhood and early adulthood relatively better preserved. Notably, this gradient is extensive and tends to affect equally memory for personal events (Rensen et al., 2017) and memory for personal and public semantic information (for review, see Race & Verfaellie, 2012). Faulty memory retrieval and memory monitoring processes are thought to be an important mechanism underlying patients’ retrograde amnesia, and consistent with this notion, patients often perform better on recognition tasks than on recall tasks. Yet, how to account for the presence of such an extensive temporal gradient has been less clear. It was initially proposed that the graded pattern might be due to the development of a progressive anterograde amnesia during the alcoholic premorbid period (Albert, Butters, & Brandt, 1981; Cohen & Squire, 1981), which might be superimposed on a strategic retrieval deficit that affects memories regardless of their age. However, this proposal was refuted by the case study of a respected scientist, who had written an autobiography in the several years just prior to Wernicke encephalopathy onset. This patient also displayed a temporally graded loss of information drawn from his autobiography – information that clearly had been encoded adequately (Butters & Cermak, 1986). An alternative possibility is that a retrieval deficit alone can lead to a graded pattern of impairment. Namely, recent memories may be more susceptible to retrieval failure than remote ones, given that they have been rehearsed less frequently (Race & Verfaellie, 2012). Another clinical feature of Korsakoff syndrome is confabulation. Whereas spontaneous confabulation is mostly seen in the acute Wernicke’s phase, provoked confabulation (i.e., confabulation in the context of a challenge to memory) is commonly seen in the chronic phase. Such confabulatory responses have also been linked to controlled aspects of memory retrieval, although results remain inconclusive (Borsutzky, Fujiwara, Brand, & Markowitsch, 2008; Kessels, Kortrijk, Wester, & Nys, 2008). III.5. Transient Global Amnesia Transient global amnesia (TGA) is defined by the sudden onset of anterograde and retrograde amnesia lasting up to 24 hours (for review, see Bartsch & Butler, 2013). It is almost always preceded by a period of intense emotional or bodily stress (Bartsch et al., 2006; Erkelens & Snoek, 2010). In general, patients with TGA display little insight into their deficits but may exhibit some anxiety and perplexity, asking self-orientation questions such as “Where are we? What day is it?” Headache, nausea, or dizziness are also relatively common accompanying complaints (Hodges & Warlow, 1990). A number of etiologies of TGA have been proposed including ischemia, migraine-related mechanisms, and epileptic phenomena. The pattern of memory deficits displayed during TGA is similar to hippocampal amnesia (Bartsch & Butler, 2013). It is characterized by severe anterograde amnesia, with information retained for a few seconds but rapidly lost with distraction (Bartsch et al., 2010; Jäger, Bäzner, Kliegel, Szabo, & Hennerici, 2009). The deficit has been shown to affect recollection, with sparing of familiarity-based processes (Jäger, Szabo, et al., 2009). A moderately severe retrograde amnesia for autobiographical events is also apparent during TGA, with striking impairment of recent memories, but also affecting memories of events that occurred up to 30 to 40 years prior, albeit less severely (Bartsch, Dohring, Rohr, Jansen, & Deuschl, 2011). Anterograde memory typically recovers gradually over the course of a week, with complete long-term recovery. Retrograde amnesia tends to recover even more quickly, but patterns of recovery vary across patients (Jäger, Bäzner, et al., 2009). Recent high-resolution MRI studies using diffusion-weighed or T2 sequences have revealed small lesions restricted to the CA1 subfield of the hippocampus that become apparent 24 to 72 hours after the episode (Bartsch et al., 2006; Scheel, Malkowsky, Klingebiel, Schreiber, & Bohner, 2012). These lesions usually disappear within 14 days, with no long-term sequelae (Bartsch & Deuschl, 2010). Metabolic or cytotoxic stress, to which CA1 cells are selectively vulnerable, constitutes the leading hypothesis of TGA pathophysiology, but the exact mechanisms remain unclear (for review, see Spiegel et al., 2017). Conclusions The study of patients with amnesia has proven fertile ground for elucidating the role of specific brain regions in normal and disordered memory. Although distinct etiologies can be associated with varying neuropsychological profiles, a core amnesic syndrome is shared among them that can be traced to disruption of the extended hippocampal system. This system comprises the hippocampus, mammillary bodies, anterior thalamic nuclei, cingulate gyrus, retrosplenial and parahippocampal cortices, and key white matter tracts that connect these regions, including the fornix, mammillothalamic tract, and cingulum bundle. The hallmark of amnesia is an inability to form new long-term memories, whether reflecting specific events (episodic memory) or novel facts or concepts (semantic memory). Nonetheless, limited acquisition of semantic knowledge may be possible via inefficient neural routes involving direct cortical learning or a perirhinally mediated sense of familiarity. Regardless of etiology, retrograde amnesia is also present, which most strikingly compromises the retrieval of premorbid episodic memories. The retrieval of premorbid semantic memories is more variably affected, with temporally limited impairment following hippocampal lesions, and more extensive impairment with involvement of neocortical storage sites, in particular anterolateral temporal cortex. The pattern of cognitive deficits associated with the amnesic syndrome has been refined over the past decade, with recent research uncovering impairments in domains other than long-term memory, including perception, short-term memory, and simulation of hypothetical or future events. The question has been raised whether these impairments are secondary to a fundamental deficit in long-term memory or reflect a more basic core function that is shared between long-term memory and these other domains. Although impairments in the construction of simulated events could reflect failure to access appropriate long-term memory representations, such failure alone does not account for impairments when relevant building blocks are provided. Furthermore, impairments in perception and short-term memory cannot easily be understood in terms of demands on long-term learning. Rather, this array of deficits points to a core binding mechanism that enables the construction of associative representations that are hierarchically organized within the MTL, and that are critical both for memory and for other cognitive functions. As demands on complex and precise binding increase, deficits beyond the domain of long-term memory become apparent in amnesia. With the advent of advanced neuroimaging, it has become possible to identify patients with lesions to discrete hippocampal subfields. Evaluation of such patients using behavioral paradigms with well-specified cognitive demands has only recently begun, but yields the exciting prospect of testing hypotheses – derived from functional neuroimaging studies – about the necessity of these regions for specific neural computations. In the same vein, neuroimaging studies have postulated distinct roles for the anterior and posterior hippocampus (Poppenk, Evensmoen, Moscovitch, & Nadel, 2013; Sheldon & Levine, 2016), a distinction that remains to be explored in human amnesia studies. Despite advances on a number of fronts, there remain discordant findings in the literature that still await resolution. Although some contradictory findings may be due to differences in behavioral paradigms and scoring methods, another potential explanation lies in lesion variability among amnesic patients. In addition to the need to better characterize focal lesions, it will be important to consider the impact of such lesions at a network level, as functional disruption of remote regions may be key to understanding individual differences in observed patterns of impairment. Studies of patients with amnesia have been instrumental in developing theoretical models of memory. Such models, in turn, have inspired new assessment techniques in the clinic, including tests of procedural learning (Heindel, Salmon, Shults, Walicke, & Butters, 1989), measures of short-term memory that tax relational processing (Blackwell et al., 2004), and assessment of autobiographical memory (Irish et al., 2011), to name just a few. By comparison, less progress has been made in the application of memory theory to the development of treatment strategies for patients with severe memory disorders. This translational agenda poses both challenge and opportunity for students of amnesia in the years ahead. Figures Figure 1: The Extended Hippocampal Network (originally “Papez circuit”). The circuit proceeds from the subiculum of the hippocampus to the mammillary bodies (via the fornix), anterior thalamic nuclei (via the mamillary-thalamic tract), cingulate gyrus (via the cingulum bundle and internal capsule), parahippocampal cortex (via the cingulum bundle), and back to the hippocampus. A more complex system of hippocampaldiencephalic-cingulate interconnections provides direct connections from the hippocampus to the cingulate cortex and anterior thalamic nuclei – this system is not represented here for clarity. An anterior coronal slice of the hippocampus and parahippocampal gyrus is also depicted, with hippocampal subfields. The parahippocampal gyrus is composed of the entorhinal cortex and perirhinal cortex anteriorly, but becomes the parahippocampal cortex more posteriorly. Figure 2: Functional division of the Medial Temporal Lobe (MTL) after Diana, Yonelinas, & Ranganath (2007). The hippocampus is at the top of the hierarchy of information processing, receiving “What” information from the ventral stream that culminates in the perirhinal cortex (item representations that can support familiarity), and “Where” information from the dorsal stream that culminates in the parahippocampal cortex (context representations). The hippocampus integrates information from both streams into memory representations that encompass item-incontext information, necessary for recollection.