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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
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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
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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
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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
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