A. Randall eMcIntosh

Brian eLevine

Gary R. Turner

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Anthony R. McIntosh

Brian Levine

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Frontiers in Systems Neuroscience

Dissecting Altered Functional Engagement in TBI and Other Patient Groups through Connectivity Analysis: One Goal, Many Paths (A Response to Hillary)

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SYSTEMS NEUROSCIENCE
Dissecting altered functional engagement in TBI and other 
patient groups through connectivity analysis: one goal, many 
paths (a response to Hillary)
Gary R. Turner1*, Anthony R. McIntosh2,3 and Brian Levine2,3,4
1 Faculty of Health, Department of Psychology, York University, Toronto, ON, Canada
2 Department of Psychology, University of Toronto, Toronto, ON, Canada
3 Rotman Research Institute, Baycrest Center for Geriatric Care, Toronto, ON, Canada
4 Faculty of Medicine, Department of Neurology, University of Toronto, Toronto, ON, Canada
*Correspondence: grturner@yorku.ca
A commentary on
Determining the nature of prefrontal 
cortex recruitment after traumatic brain 
injury: a response to Turner
by Hillary, F. G. Front. Sys. Neurosci. 5:24. 
doi: 10.3389/fnsys.2011.00024
We are grateful to Hillary for his detailed 
commentary on our article (Turner et al., 
2011), which gives an opportunity to clarify 
some of the main points of the article. We are 
pleased that Hillary underscores the main 
interpretation of our data, which is that 
augmented neural activity is compensatory 
and does not reflect brain reorganization, 
and that the behaviorally relevant regions 
recruited in TBI are also functionally rele-
vant in healthy adults at a higher level of task 
difficulty. Hillary (2011) notes that the inno-
vation of this altered functional engagement 
hypothesis is “not entirely clear.” We do not 
claim ownership of the intellectual history of 
this notion, which has been invoked in many 
contexts, including in theories of natural 
recovery, and rehabilitation in brain injury 
(Backman and Dixon, 1992; Robertson and 
Murre, 1999). Indeed, empirical support for 
this notion was demonstrated in the early 
days of functional neuroimaging (Wood 
et al., 1980) in patients with stroke (Weiller 
et al., 1992; Engelien et al., 1995; Buckner 
et al., 1996) and dementia (Bookheimer 
et al., 2000). We showed similar findings in 
a case study of TBI more than a decade ago 
(Levine et al., 1998). The altered functional 
engagement idea has also been extensively 
discussed in the neurocognitive aging litera-
ture (e.g., Cabeza et al., 1997; Reuter-Lorenz 
et al., 2000; Rypma and D’Esposito, 2000). 
As we noted in our paper, this interpretation 
does not necessarily follow from activation 
maps; it is supported by analysis of corre-
lations between brain signal and behavior, 
between brain signals from different regions 
(i.e., functional connectivity), and between 
functional connectivity and behavior. These 
concepts were empirically tested in patients 
with Alzheimer’s disease as early as 2003 
with the seed-behavioral PLS technique 
(Grady et al., 2003a,b), which served as a 
model for our paper.
Hillary made several criticisms of our 
paper, which we will address in order:
(1) “The authors define ‘activation’ in their 
study as the relationship between the 
fMRI signal and task accuracy; this the 
fMRI signal is modeled solely as it rela-
tes to task accuracy.”
It is inappropriate to define the corre-
lation of task accuracy to fMRI signal as 
“activation” and in fact we did not do so in 
our paper. Moreover, the assertion that we 
modeled the fMRI signal solely in relation to 
task accuracy is incorrect. In behavioral PLS 
and seed-behavioral PLS, the mean BOLD 
response to the events of interest (task 
demands, seed-connectivity) are extracted 
for each subject, then correlated with accu-
racy across subjects.
(2) “The authors are also unlikely to 
observe all possible neural resources 
that are differentially recruited after 
injury. For example, there may be neu-
ral responses that hold non-linear rela-
tionships with accuracy or are related 
only to reaction time.”
We admit to being unable to observe “all 
possible neural resources that are differen-
tially recruited after injury,” and we consider 
any such claim to be ludicrous. Our paper 
was focused on the change in functional 
connectivity as it relates to group and behav-
ior. Thus our seed-behavior PLS delineated 
patterns of connectivity that differentially 
related to behavior across the two groups. 
Turning to reaction time, this was not a 
relevant measure for the working memory 
task that we used, which is a well-validated 
and established task of  differential executive 
demands in working memory in the fMRI 
environment. These differential demands 
are determined at the encoding (number of 
items) and manipulation (alphabetize versus 
retain) phases of the task. Reaction time at 
the probe phase is irrelevant to the execu-
tive demand manipulations in this task and 
therefore would not have been an appropri-
ate measure to include in our analyses.
(3) “The problem is that the authors have 
no way to identify prefrontal invol-
vement after TBI that is not correla-
ted with performance, an outcome 
that could be a candidate for brain 
reorganization.”
This statement is incorrect. First, we 
conducted a whole-brain analysis of task-
related activity (irrespective of perfor-
mance) in our prior paper (Turner and 
Levine, 2008). With respect to the current 
paper, the seed-behavior PLS identified 
connectivity patterns that were both related 
to and not related to performance. As seen 
in Figure 3 of our original work (Turner et 
al., 2011), whole-brain functional connec-
tivity with the left BA 44 seed was not corre-
lated with behavior for all conditions except 
for the Alphabetize 3 condition in patients 
with TBI. Regions functionally connected 
to the left BA 46 ROI were also not corre-
lated with performance for the Alphabetize 
5, Maintain 3, and Maintain 5 conditions 
in the TBI group. This is a key point of our 
paper: following brain injury, some func-
tional connections within PFC are related to 
performance, and some are not. Moreover, 
PLS is a data-driven approach. It is entirely 
possible, if there was brain reorganization, 
Frontiers in Systems Neuroscience www.frontiersin.org March 2012 | Volume 6 | Article 10 | 1
General Commentary
published: 07 March 2012
doi: 10.3389/fnsys.2012.00010
for this analysis approach to yield a latent 
variable delineating areas of connectivity 
that were both functionally connected and 
behaviorally relevant in TBI and not in con-
trols. This pattern did not emerge in the 
data-driven analysis, but there was nothing 
in this approach to prevent such a pattern 
from emerging if it was present.
(4) “The results from this approach may 
be misleading given that variance in 
accuracy data is artificially restricted in 
fMRI studies; investigators must gua-
rantee high accuracy rates to ensure 
task compliance.”
All groups were off ceiling for all condi-
tions, except for the controls in the Maintain 
3 condition. As discussed in Note 1 (p. 5) 
even here, the brain–behavior correlations 
were significant. While interpretation of 
the Maintain 3 condition should take this 
restriction of variance into consideration, 
this does not affect the interpretation of 
results from other conditions, which were 
key to overall interpretation of the brain–
behavior correlations.
(5) The authors argue that recruitment of 
resources after injury can be compen-
satory, but only under some conditions. 
For example, they conclude that neural 
recruitment at lower task loads may be 
compensatory, but that increased pre-
frontal involvement at higher task loads 
in TBI is attributable to “poor regula-
tion of functional brain activity.”
We actually hold that altered functional 
engagement is compensatory not just at the 
earlier levels of task difficulty, but also at 
the higher levels, as illustrated in Figure 3 
(Turner et al., 2011), where positive cor-
relations with seed-connectivity can be 
seen in TBI patients across all levels of 
task difficulty. We have previously framed 
augmented activation as reflecting a gener-
alized reduction in efficiency of brain func-
tion at all levels. That is, the system is not 
well regulated if it is engaged at lower levels 
of task demand (Turner and Levine, 2008). 
While our statement of poor regulation in 
response to increasing task loads may have 
been read as reflecting a viewpoint that the 
poor regulation applies only to higher task 
demands, this was not our intention.
(6) “It is equally dubious that functional 
engagement of prefrontal areas differs 
at each task load yet activation at all 
loads remains correlated with the same 
performance variable.”
The fundamental principle behind this 
assertion relates to degeneracy (Mesulam, 
1998; Price and Friston, 2002), which holds 
that there is more than one way for the brain 
to accomplish the same behavior, and also 
that a single brain systems can be engaged 
in multiple tasks. There are redundant 
systems for even basic functions, such as 
vision or perception, that can be differen-
tially engaged to accomplish the same task. 
The application of this principle broadens 
when considering the same behavior across 
conditions as in our task, where we high-
light differential brain network connectivity 
supporting accuracy in conditions of high 
versus low executive demand.
Summary
We are grateful for the opportunity to 
clarify the misconceptions contained in 
Hillary’s commentary. We agree that there 
are multiple routes to understanding altered 
functional brain activity in TBI and other 
patient groups. There is no standard analyt-
ical framework that is broadly accepted. We 
applied one approach that has been success-
fully applied in other patient groups (Grady 
et al., 2003a,b) and in manipulations with 
healthy subjects (for review, see McIntosh 
et al., 2004; Krishnan et al., 2011). There 
is no approach that is without limitations. 
We are encouraged by the recent increase 
in research in this domain and welcome the 
alternative frameworks as applied by other 
researchers.
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Received: 22 January 2012; accepted: 09 February 2012; 
published online: 07 March 2012.
Citation: Turner GR, McIntosh AR and Levine B (2012) 
Dissecting altered functional engagement in TBI and other 
patient groups through connectivity analysis: one goal, 
many paths (a response to Hillary). Front. Syst. Neurosci. 
6:10. doi: 10.3389/fnsys.2012.00010
Copyright © 2012 Turner, McIntosh and Levine. This is 
an open-access article distributed under the terms of the 
Creative Commons Attribution Non Commercial License, 
which permits non-commercial use, distribution, and repro-
duction in other forums, provided the original authors and 
source are credited.
Turner et al. Altered functional engagement in TBI
Frontiers in Systems Neuroscience www.frontiersin.org March 2012 | Volume 6 | Article 10 | 2


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Dissecting Altered Functional Engagement in TBI and Other Patient Groups through Connectivity Analysis: One Goal, Many Paths (A Response to Hillary)

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