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3106 | Brain 2014: 137; 3100–3108 designers, who are keen to identify treatment effects over intervals that are as short as possible. Ultimately, defining which features of image acquisition and analysis promote reproducible studies and metrics of brain connectivity will make it easier to integrate, coordinate, and meta-analyse connectivity data across disparate studies that were initially designed independently. The broad interest in methods to assess brain connectivity relative to other measures associated with ageing and dementia suggests that major advances are imminent, revealing new factors that influence brain network changes in the millisecond range, across the entire human lifespan and as a result of neurodegenerative disease. Acknowledgements The authors would like to thank Yonggang Shi of the Laboratory of Neuro Imaging for preparation of Fig. 1. Funding Work related to this commentary was supported by the National Institutes of Health (Rosen), R01MH094343, and P41EB015922 to A.W.T. Arthur W. Toga and Paul M. Thompson Laboratory of Neuro Imaging, University of Southern California Correspondence to: Arthur Toga E-mail: [email protected] doi:10.1093/brain/awu276 Scientific Commentaries References Agosta F, Pievani M, Geroldi C, Copetti M, Frisoni GB, Filippi M. Resting state fMRI in Alzheimer’s disease: beyond the default mode network. Neurobiol Aging 2012; 33: 1564–78. Andrews-Hanna JR, Reidler JS, Sepulcre J, Poulin R, Buckner RL. Functional-anatomic fractionation of the brain’s default network. Neuron 2010; 65: 550–62. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Res Med 1995; 34: 537–41. Braak H, Braak E. Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1991; 1: 213–6. Dennis EL, Jahanshad N, Toga AW, McMahon KL, de Zubicaray GI, Martin NG, et al. Development of brain structural connectivity between ages 12 and 30: a 4-tesla diffusion imaging study in 439 adolescents and adults. Neuroimage 2013; 64: 671–84. Dosenbach NU, Nardos B, Cohen AL, Fair DA, Power JD, Church JA, et al. Prediction of individual brain maturity using fMRI. Science 2010; 329: 1358–61. Greicius M. Resting-state functional connectivity in neuropsychiatric disorders. Curr Opin Neurol 2008; 21: 424–30. Hedden T, Van Dijk KRA, Becker JA, Mehta A, Sperling RA, Johnson KA, et al. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci 2009; 29: 12686–94. Jahanshad N, Toga AW, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, et al. Connectome-wide genome-wide search discovers SPON1 gene variant influencing dementia severity. PNAS 2013; 110: 4768–73. Lim HK, Nebes R, Snitz B, Cohen A, Mathis C, Price J, et al. Regional amyloid burden and intrinsic connectivity networks in cognitively normal elderly. Brain 2014; 137: 3320–31. Mormino EC, Smiljic A, Hayenga AO, Onami Sh, Greicius MD, Rabinovici GD, et al. Relationships between beta-amyloid and functional connectivity in different components of the default mode network in aging. Cereb Cortex 2011; 21: 2399–407. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. PNAS 2001; 98: 676–82. van den Heuvel MP, Sporns O. Rich-club organization of the human connectome. J Neurosci 2011; 31: 15775–86. The hippocampus is essential for completely unconscious as well as conscious flexible memories This scientific commentary refers to ‘Unconscious relational encoding depends on hippocampus’ by Duss et al. (doi: 10.1093/brain/awu270). Several beliefs about the nature of organic amnesia were deeply entrenched by the early 1990s. It was believed that damage to the medial temporal lobe or its connections in the midline diencephalon and basal forebrain did not disrupt intelligence, perception, processing of information at input and immediate (short-term) memory, but selectively disrupted—following even a brief distraction—recall and recognition of recently encountered personal events or facts/concepts. In other words, amnesia was thought to affect only episodic and semantic memory, whether for pre-morbid events (retrograde amnesia) or post-morbid events (anterograde amnesia). With these kinds of memory, not only is the remembered information consciously apprehended at input and at retrieval, but the person remembering is also consciously aware that the information is a memory. That is, the person feels that the information has been encountered before, often in a particular context. In contrast, it was believed that Scientific Commentaries amnesics acquired and retained other kinds of memory, such as habits and skills, normally. Although these latter types of non-declarative memory are functionally heterogeneous, they all lack the conscious feeling of memory that accompanies episodic and semantic memory. Since the late 1990s, several of these entrenched beliefs have been challenged. On the one hand, it has been argued that amnesia is not functionally unitary: while disruption of the hippocampal, fornix and anterior thalamic system impairs recall of flexible (relational) associative memories, disruption of the perirhinal cortex or its dorsomedial thalamic projection impairs inflexible item familiarity (for a review, see Montaldi and Mayes, 2010). Relational memory representations have components linked to each other as well as to other representations, which allows flexible access through multiple cues both to the representation and from it to other representations (Cohen and Eichenbaum, 1993). Rigid representations lack these componential links that allow flexible two-way access to much stored information. On the other hand, it has been argued that some kinds of function are not preserved as claimed. These include high-level visual perception (e.g. Lee et al., 2012) and immediate memory for item-location associations (e.g. Pertzov et al., 2013). Another strong belief that has been challenged is that priming is preserved in organic amnesics. This challenge is of particular interest because priming is a kind of unconscious memory for specific kinds of information involving items and/or associations, for which there can also be recall and recognition, i.e. conscious memory. The unconscious memory is revealed by faster, more accurate or altered processing of previously encountered items or associations even when these are not recognized or recalled. This implies that, if priming is preserved in amnesics, they must have preserved unconscious memory for previously encountered items or associations, even though their conscious memory for the same stimuli is impaired. Although conscious and unconscious memory of a given stimulus probably depend on partially distinct encoded stimulus features, some overlap between the kinds of information that support recognition and priming of the same nominal stimulus seems likely: overlap can be adjusted by selecting appropriate recognition foils to match the information that priming is based on. So, if priming is preserved, there is a problem for the dominant view that hippocampal system dysfunction disrupts storage of complex associative inputs. If priming is preserved, then amnesics are not so much impaired at storing new episodic and semantic information as unable to generate conscious memory for these things. Challenges to the view that priming is preserved in amnesia typically focus on novel associations, such as the link between previously unrelated words or object pictures. If subjects are able to make judgements about pairs of stimuli studied together (e.g. which is bigger) faster than about otherwise similar pairs that were not studied together, that is evidence of priming. Although metaanalysis has revealed that amnesics show intact priming for previously familiar items, they are impaired relative to matched controls at priming of novel associations (Gooding et al., 2000). However, Brain 2014: 137; 3100–3108 | 3107 this does not prove that hippocampal damage impairs novel associative priming because healthy people will recall or recognize many more studied pairs than amnesics and may use this conscious memory to enhance their ‘primed’ performance. It is very difficult to control for this potential confound because joint tests of associative recognition and associative priming interfere with each other (Spencer et al., 2009). For some years, Henke and her colleagues have been developing a priming paradigm that completely avoids this confound and also, unlike standard priming, clearly shows evidence of unconscious relational priming that may depend on the hippocampal system. They have presented novel associations between words or pictures very briefly with a preceding and following mask so that participants are not consciously aware of which stimuli they have been shown. In a subsequent test, where they must consciously identify pairings of components that are related in a semantic way to the unconsciously studied pair, their judgements are altered for pairs related to those studied relative to similar but unrelated pairs. For example, Reber et al. (2012) subliminally showed transitively-related word pairs (A–B and B–C) or unrelated pairs (E–F and G–H). A minute later participants were supraliminally shown pairs that were either transitively related like A–C or unrelated like E–H, and had to judge whether the words were semantically related. They more often judged transitively related pairs to be related semantically. Hippocampal activity was higher during unconscious encoding of transitively related pairs and during the unconscious retrieval of such pairs. This inferential unconscious memory is clearly relational, although functional MRI correlations cannot prove that hippocampal activity is essential for it. To do this requires a lesion approach. Duss et al. (2014) in this issue of Brain, have now addressed this matter. They found that 11 amnesics with hippocampal system damage were not only impaired at unconscious relational associative verbal memory, but also at an indirect memory test where they remained conscious of the primed stimuli at both study and test. Participants were subliminally shown unrelated word pairs like ‘violin–lemon’ and ‘table–car’ up to nine times for 17 ms each time with masks immediately before and after. At test 5 min later, they were supraliminally shown pairs either related to those previously seen, such as ‘cello–mandarin’, or unrelated, such as ‘harp–truck’. Following nine presentations, the controls judged the related pairs to be semantically related more often than they did the unrelated pairs, whereas the patients, as a group, did not. However, the patients performed normally at another task at which they were also never conscious of the subliminally studied words. In this task, subliminal presentation of a single word like ‘fisher’ was followed immediately by supraliminal presentation of a related word (e.g. ‘angler’) or an unrelated word (e.g. ‘credit’), and participants were required to judge the pleasantness of the latter. It took significantly longer to judge pleasantness for related test words, but the effect was the same in amnesics and their controls. The authors plausibly argue that the impaired unconscious associative memory was relational and dependent on the hippocampal system. In contrast, the preserved 3108 | Brain 2014: 137; 3100–3108 unconscious semantic single-word memory comprised rigidly bound components; it was therefore not relational and depended not on the hippocampal system, but on prefrontal language areas. These anatomical conclusions were mainly based on extensive MRI investigation of all the controls and six of the patients who proved scannable, using structural MRI with manual hippocampal volumetry and voxel-based morphometry, functional MRI and resting state functional MRI. The patients had a mixture of hippocampal, fornix and/or anterior thalamic nucleus damage or had aetiologies (Herpes simplex or hypoxia) consistent with such damage. Even if structurally intact, the hippocampus would not have been functionally normal (Snaphaan et al., 2009). Unconscious relational memory in the controls probably required good hippocampal functional connections to several structures, including the anterior temporal neocortex, which plays a role in semantic memory processing. Strikingly, three high-performing patients, unlike the other eight, showed preserved unconscious relational memory; their residual hippocampus also showed a similar, but weaker, pattern of connectivity to that of controls, whereas the other scanned, but impaired, patients did not. The authors argue that, if the hippocampus and its key connections are working above a critical level, unconscious relational memory can be supported normally, although conscious relational memory is greatly impaired. This strongly suggests that relational memory, whether conscious or unconscious, is critically dependent on processing and perhaps storage mediated by the hippocampal system, but that good unconscious memory, being much weaker, requires far fewer of that system’s resources. Replications of this important study are desirable in patients with more confined hippocampal system damage, such as otherwise matched patients with different degrees of fornix damage. However, lesion differences outside the hippocampal system in, for example, parts of visual cortex, did not differ consistently between high-performing and impaired patients, which suggests that such damage did not disrupt unconscious relational memory. A problem remains with the relationship between the completely unconscious kind of relational priming and novel associative priming where there is consciousness of studied stimuli. Preserved amnesic performance has recently been reported for the latter kind of priming (Verfaellie et al., 2012). Duss et al. suggest that the amnesics in that study may have had sufficient residual hippocampal functionality to perform normally. This proposal needs testing but would be more plausible if associative priming was less relational in the Verfaellie et al. (2012) study. Although identifying Scientific Commentaries associative or even item memories as relational is not easy, being relational is probably a matter of degree. This warrants further investigation, as do the preserved kinds of non-relational priming, which, unlike item familiarity memory and despite conflicting evidence, Duss et al. argue may be unaffected by perirhinal cortex lesions. Unless this is wrong, in contrast to relational memory, different neural systems must mediate conscious and unconscious non-relational memory. Andrew Mayes University of Manchester, UK Correspondence to: Andrew Mayes. E-mail: [email protected] doi:10.1093/brain/awu284 References Cohen NJ, Eichenbaum H. Memory, amnesia and the hippocampal system. Cambridge: MIT Press; 1993. Duss SB, Reber TP, Hanggi J, Schwab S, Wiest R, Muri RM, et al. Unconscious relational encoding depends on hippocampus. Brain 2014; 137: 3348–63. Gooding PA, Mayes AR, van Eijk R. A meta-analysis of indirect memory tests for novel material in organic amnesics. Neuropsychologia 2000; 38: 666–76. Lee ACH, Yeung LK, Barense MD. The hippocampus and visual perception. Front Hum Neurosci 2012; 6: 1–17. Montaldi D, Mayes AR. The role of recollection and familiarity in the functional differentiation of the medial temporal lobes. Hippocampus 2010; 20: 1291–314. Pertzov Y, Miller TD, Gorgoraptis N, Caine D, Schott JM, Butler C, et al. Binding deficits in memory following temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis. Brain 2013; 136: 2474–85. Reber TP, Luechinger R, Boesiger P, Henke K. Unconscious relational inference recruits the hippocampus. J Neurosci 2012; 32: 6138–48. Snaphaan L, Rijpkema M, van Uden I, Fernandez G, de Keeuw FE. Reduced medial temporal lobe functionality in stroke patients: a functional magnetic resonance imaging study. Brain 2009; 132: 1882–88. Spencer TJ, Montaldi D, Gong QY, Roberts N, Mayes AR. Object priming and recognition memory: dissociable effects in left frontal cortex at encoding. Neuropsychologia 2009; 47: 2942–7. Verfaellie M, LaRocque KF, Keane MM. Intact implicit verbal relational memory in medial temporal lobe amnesia. Neuropsychologia 2012; 50: 2100–6.