Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

Miller, Thomas D.; Chong, Trevor T.‐J.; Davies, Anne M. Aimola; Ng, Tammy; Johnson, Michael R.; Irani, Sarosh R.; Vincent, Angela; Husain, Masud; Jacob, Saiju; Maddison, Paul; Kennard, Christopher; Gowland, Penny; Rosenthal, Clive R.

doi:10.1093/brain/awx070

Cited by 102 publications

(101 citation statements)

References 29 publications

(46 reference statements)

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“…In line with previous reports of this patient population (Dalmau and Rosenfeld, 2014;Miller et al, 2017), manual (blinded) segmentation of the hippocampi from high-resolution structural MRI scans confirmed that our patients showed volume loss confined to the left (Patients -HPC: 2506mm 3 (mean) +/-394 (standard deviation), control participants -CTL: 3173 mm 3 +/-339, W=4.0, p=0.002) and right (HPC: 2678mm 3 +/-528, CTL: 3286mm 3 +/-301, W=8.0, p=0.01) hippocampus. To rule out pathological differences between patients and controls elsewhere in the brain, an automated voxel-based-morphometry (VBM; Ashburner, 2009) analysis was carried out on whole brain T1 weighted MRI images and, in line with previous reports on patients of this sort (Wagner et al, 2015;Finke et al, 2017;Miller et al, 2017), did not result in any significant group differences outside of the hippocampus even at a liberal uncorrected p-value of less than 0.001. Neuropsychologically, the patients displayed an impairment in immediate and delayed recall on the Logical Memory (short stories) test (Wechsler, 1997), and they recollected significantly fewer episodic ('internal'), but not semantic ('external') details on the Autobiographical Interview , as detailed in Table 2.…”

Section: Participantssupporting

confidence: 92%

Mind-wandering in people with hippocampal damage

McCormick

Rosenthal

Miller

et al. 2017

Preprint

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Acknowledgments:We thank all the participants, particularly the patients and their relatives, for the time and effort they contributed to this study. We also thank the consultant neurologists: Drs. M.J. Johnson, S.R. Irani, S. Jacobs and P. Maddison. We are grateful to Martina F. Callaghan for help with MRI sequence design, Trevor Chong for second scoring the Autobiographical Interview, Alice Liefgreen for second scoring the mind-wandering thoughts, and Elaine Williams for advice on hippocampal segmentation. E.A.M. and C.M. are supported by a Wellcome Principal Research Fellowship to E.A.M. (Abstract Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking and problem-solving, and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mindwandering and identifying the associated neural networks. Two prominent features of mindwandering are mental time travel and visuo-spatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateralhippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally-mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond memory, placing it at the heart of human mental life. Significance statementHumans tend to mind-wander about 30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuo-spatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering 3 in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene-based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond memory, placing it at the heart of our mental life.

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Section: Participantssupporting

confidence: 92%

Mind-wandering in people with hippocampal damage

McCormick

Rosenthal

Miller

et al. 2017

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“…Hence, this increasingly well‐characterized group of patients may represent an important neuropsychological model of disrupted functional connectivity whose critical locus resides within the hippocampus. This is broadly consistent with other studies who have reported selective hippocampal damage in VCKCC_Ab LE patients, perhaps even at the level of the hippocampal subfields (Miller et al, ). As such, future neuropsychological studies with VCKCC_Ab LE patient cohorts, in combination with studies utilizing high‐resolution structural and functional MRI and advanced analytical methods, could offer important traction on many of the entrenched impasses firmly rooted in the hippocampal literature.…”

supporting

confidence: 92%

“…This dissociation is consistent with the recently reported dissociation F I G U R E 1 Structure MRI of patients from initial presentation in the acute phase (T2 coronal FLAIR; left column) and at time of neuropsychological testing in the acute phase (T1 coronal; right column). White arrows indicate increased signal intensity in the left column and subsequent atrophy in the right column (as reported by neuroradiologists) between episodic and semantic memory impairment/preservation observed in a group of 16 LGI1-VGKCC-Ab LE patients (Miller et al, 2017). Moreover, at the group level, and contrary to the standard consolidation model, our VGKCC-Ab LE patients demonstrated no temporal-gradient when recalling past personal memories.…”

supporting

confidence: 59%

“…In this study, we assess a homogenous population with a highly discrete hippocampal lesion that is clinically stable after an acute phase: patients with voltage‐gated potassium channel complex antibody related limbic encephalitis (VGKCC‐Ab LE) (Finke et al, ; Miller et al, ). VGKCC‐Ab LE is a rare autoimmune condition discovered in 2004 with a prevalence of about 1 in 400,000 (Vincent et al, ).…”

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confidence: 99%

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Characterizing memory loss in patients with autoimmune limbic encephalitis hippocampal lesions

et al. 2019

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Since the publication of Scoville and Milner's (1957) seminal paper, the precise functional role played by the hippocampus in support of human memory has been fiercely debated. For instance, the single question of whether the hippocampus plays a time‐limited or an indelible role in the recollection of personal memories led to a deep and tenacious schism within the field. Similar polarizations arose between those who debated the precise nature of the role played by the hippocampus in support of semantic relative to episodic memories and in recall/recollection relative to familiarity‐based recognition. At the epicenter of these divisions lies conflicting neuropsychological findings. These differences likely arise due to the consistent use of heterogeneous patient populations to adjudicate between these positions. Here we utilized traditional neuropsychological measures in a homogenous patient population with a highly discrete hippocampal lesion (i.e., VGKCC‐Ab related autoimmune limbic encephalitis patients). We observed consistent impairment of recent episodic memories, a present but less striking impairment of remote episodic memories, preservation of personal semantic memory, and recall but not recognition memory deficits. We conclude that this increasingly well‐characterized patient group may represent an important homogeneous population in which the functional role played by the hippocampus may be more precisely delineated.

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“…For example, some studies suggest that DG and CA 2/3 , respectively, subserve pattern separation and completion, although there is disagreement about this distinction (Chadwick et al, ; Guzowski, Knierim, & Moser, ; Myers & Scharfman, ; Yassa & Stark, ). Evidence from healthy adults (Chadwick et al, ; Hebscher et al, in press) and patients (Miller et al, ) for the role of CA 2/3 or CA 3 alone in episodic memory and AM suggests that our results may be accounted for by the CA 3 region and not the DG.…”

Section: Introductionmentioning

confidence: 62%

Episodic autobiographical memory is associated with variation in the size of hippocampal subregions

Palombo

Bacopulos²,

Amaral

et al. 2018

Hippocampus

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Striking individual differences exist in the human capacity to recollect past events, yet, little is known about the neural correlates of such individual differences. Studies investigating hippocampal volume in relation to individual differences in laboratory measures of episodic memory in young adults suggest that whole hippocampal volume is unrelated (or even negatively associated) with episodic memory. However, anatomical and functional specialization across hippocampal subregions suggests that individual differences in episodic memory may be linked to particular hippocampal subregions, as opposed to whole hippocampal volume. Given that the DG/CA circuitry is thought to be especially critical for supporting episodic memory in humans, we predicted that the volume of this region would be associated with individual variability in episodic memory. This prediction was supported using high-resolution MRI of the hippocampal subfields and measures of real-world (autobiographical) episodic memory. In addition to the association with DG/CA , we further observed a relationship between episodic autobiographical memory and subiculum volume, whereas no association was observed with CA or with whole hippocampal volume. These findings provide insight into the possible neural substrates that mediate individual differences in real-world episodic remembering in humans.

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Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

Cited by 102 publications

References 29 publications

Mind-wandering in people with hippocampal damage

Mind-wandering in people with hippocampal damage

Characterizing memory loss in patients with autoimmune limbic encephalitis hippocampal lesions

Episodic autobiographical memory is associated with variation in the size of hippocampal subregions

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