Although the experimental study of memory can be traced to Hermann Ebbinghaus, William James, and others in the last two decades of the 19th century, these approaches were neglected in patient studies until the famous studies of Brenda Milner and others starting in the 1950s. Before that, though, there were numerous case reports of memory disorders with enough clinical description and accompanying postmortem examination to illuminate some critical elements of the brain's memory networks.
Theodore Ribot, in The Diseases of Memory (1881), initially called attention to the nature and course of amnesia accompanying the dementias. He pointed out that the first characteristic of amnesia in patients with dementia is the loss of memory for recently experienced events with relative preservation of remote events, an observation later termed ‘Ribot's law' in reference to the temporal gradient commonly observed in retrograde amnesias.
In the late 1880s and 1890s, Russian psychiatrist Sergei Korsakoff described a series of patients, mostly alcoholics, with a neuropsychiatric syndrome prominently involving memory loss. The characteristic amnesia, he observed, involved a disturbance of memory for recent events and new material, commonly with remarkably good memory for events occurring long before the illness, and often accompanied by a lack of insight into amnesia with confabulation. Patients often would repeat themselves in conversation, may not recognize the examiner from one encounter to the next, or might reconstruct an encounter with the examiner in a context that never took place.
Simultaneously with but separately from Korsakoff, German psychiatrist and pathologist Carl Wernicke described an acute clinical syndrome involving gait ataxia, opthalmoparesis, and confusion that sometimes evolved into chronic amnesia. Wernicke's encephalopathy and Korsakoff's amnesia eventually came to be recognized as different manifestations of a similar underlying condition. Wernicke's studies of the brains of his patients led to the observation that brainstem pathology was present in the vicinity of the third ventricle, and subsequent investigations by Gudden, Gamper, and others clarified the involvement of the mammillary bodies and dorsomedial nucleus of the thalamus. However, it was also clear from diminished brain weight that more than just those small regions were damaged, leading to hypotheses about cortical involvement.
Other brain regions now known to be importantly involved in episodic memory had roots in early neurologic literature, including Arnold Pick's (early 1900s) and Kahn and Thompson's observations in the 1930s that frontal lobe degeneration led to difficulties accessing ‘memory material that may be there,' and Yakovlev and Locke's observations on the thalamus and cingulate cortex in the 1960s.
In 1907, German psychiatrist and neuropathologist Alois Alzheimer reported the case of a patient who died at age 51 after progressive memory loss and cognitive change, as well as personality and behavioral decline. Application of new histologic techniques identified plaques and tangles, the hallmark pathologic features of Alzheimer's disease (AD). As these pathological features became scrutinized in further studies, it became clear from Fuller's work in the early 1900s and from Henderson and Machlachlan's work in the 1930s, as well as others, that the hippocampal formation was prominently affected.
Although Brown and Schafer had demonstrated experimentally in the 1880s that monkeys with temporal lobe lesions had impaired memory, it was Russian psychiatrist Vladimir Bekhterev who, in 1900, first reported medial temporal lobe (MTL) (uncinate gyrus and hippocampal) softening in a 40-year-old patient who died after exhibiting a profound amnesia. Fifty years later, a handful of other case reports of patients with amnesic syndromes and hippocampal pathology emerged (eg, Glees and Griffith, 1952
In 1954, Connecticut neurosurgeon William Scoville reported the profound memory loss that occurred in two patients on whom he had performed the same surgical procedure, in one to treat psychosis and in the other to treat a refractory seizure disorder (Scoville, 1954
). The surgical procedure involved the bilateral resection of the rostral MTLs, including the hippocampal formation, amygdala, and overlying cortex. Both patients developed profound amnesia, although because of emotional symptoms in the former patient the memory deficit was most obvious in the latter patient, HM.
Scoville and Brenda Milner—an English psychologist who had recently completed her training at McGill under Canadian psychologist Donald Hebb—reported in 1957 a series of 10 cases from Scoville's practice of temporal lobe resections (Scoville and Milner, 1957
). Of these cases, three were described as having a severe memory deficit—all had undergone bilateral MTL resections including the hippocampal gyrus. They were described as forgetting ‘the incidents of their daily life as fast as they occur.' The striking thing about Case 1, HM, was that his memory deficit was not only profound, including both anterograde and retrograde components with preservation of remote memory, but also isolated in the sense that other aspects of his intellect and personality were spared. shows HM's surgical lesion.
Figure 1 Two sections from a transverse MRI of HM's brain illustration location of surgical lesion, which involved the excision of the rostral portion of bilateral medial temporal lobes (arrows; areas of bright signal indicate cerebrospinal fluid). Figure courtesy (more ...)
Besides calling prominent attention to the role of the MTL in memory function, it is important to recognize that many critical observations and hypotheses regarding episodic and other forms of memory were generated through studies of a man who became one of the world's most famous neurologic patients, HM, who died on December 4, 2008, at the age of 82 (Squire, 2009
). Studies that were initiated in work with him by Brenda Milner, Suzanne Corkin, and many others led to the development of methods for measuring memory dysfunction and to seminal concepts regarding memory as a distinct, separable, localizable ability, and the brain's multiple memory systems, which are summarized extensively elsewhere (Eichenbaum and Cohen, 2001
). HM and the other early case studies also provided the initial characterization between forms of declarative memory. Thus, HM, the patients of Bekhterev, those with Korsakoff's amnesia, and patients in the early stage of AD all exhibit severe deficits in episodic memory, that is, greatly diminished ability to remember daily personal events. These findings, and in particular the work with HM that highlighted a critical role for the medial temporal area in episodic memory, provided strong motivation to develop animal models of amnesia that could better identify the critical brain areas within the MTL and the functional circuitry within and outside that area. In the following sections we will review the results of these anatomical studies as well as behavioral and physiological findings from the animal literature, then return to modern studies of the cognitive neuroscience of episodic memory in humans.