Departments of Surgery and Physiology, University of Toronto and
The Toronto Western Research Institute, Toronto, Ontario M5T 2S8,
Canada
 |
INTRODUCTION |
Where and how the human brain integrates
complex information that impact on tasks that require attention and
effortful thought is not well understood. The anterior cingulate cortex
(ACC) has been implicated in many cognitive processes, many of which
require attention (Devinsky et al. 1995
; Mesulam
1990
; Posner and Rothbart 1998
). Brain-imaging
studies have revealed that the ACC becomes activated when a subject is
performing any one of a variety of tasks that require attention
(Carter et al. 1998
; Elliott and Dolan
1998
; Paus et al. 1998
; Peterson et al.
1999
; Whalen et al. 1998
). Although brain
imaging can reveal relatively large regions of task-related changes in
blood flow and oxygenation, only inferences can be drawn about the
activity of any particular neuron. Therefore electrophysiological
studies are needed to complement imaging studies and to provide
information about function of individual ACC neurons. Unfortunately the
interpretation of task-related neuronal activity in highly trained
nonhuman primates can be problematic, and the invasive nature of
microelectrode recordings normally precludes studying the contribution
of individual neurons to cognitive networks in humans. In the present
study, we had the unique opportunity to record the activity of human
ACC neurons during awake cingulotomy procedures, which allowed us to
test the hypothesis that neurons exist within the human ACC that are
modulated by attention-demanding tasks.
There is also increasing evidence for a role of the ACC in pain
perception (Devinsky et al. 1995
; Peyron et al.
1999
; Rainville et al. 1997
), and functional
brain-imaging studies have revealed separate regions of pain- and
attention-related responses in the human ACC (Davis et al.
1997
; Derbyshire et al. 1998
; Kwan et al.
2000
). In light of our recent data of the existence of
pain-responsive neurons in the human ACC (Hutchison et al.
1999
), we tested all neurons modulated by the cognitive tasks
for responsivity to painful stimuli applied to the skin.
 |
METHODS |
Stereotactic extracellular microelectrode recordings were made
in the ACC during bilateral cingulotomy in nine patients with obsessive-compulsive disorder or depression (Table
1). In each patient, recordings were made
during one to two electrode trajectories toward the lesion target
bilaterally at 20-40 mm posterior to the anterior-most portion of the
frontal horn, near the ventral cingulate gyrus as visualized on
magnetic resonance imaging (MRI). Details of the recording procedure
have been described previously (Davis et al. 1994
;
Lozano et al. 1995
). Neuronal activity was monitored
during performance of one or more attention-demanding cognitive tasks
in a total of 36 neurons in the ACC. The attention-demanding cognitive
tasks included mental arithmetic (e.g., counting backwards by 3's),
generation of words belonging to a particular category (e.g., animals,
fruits, etc.) or beginning with a particular letter, or the Stroop test
whereby patients were instructed to name the ink color of words in a
list (e.g., the word "blue" written in red ink). The
word-generation tasks have been described previously (Davis et
al. 1997
). Prior to testing, the tasks were described to the
patients. They were then instructed to close their eyes, relax, and to
perform the tasks silently. Baseline neuronal activity was monitored
for 10-30 s prior to the first task. Each task type tested was
repeated two to four times separated by at least 10 s. The total
number of neurons tested for responsiveness in each task were: Stroop
(n = 7), categories (n = 16), letters
(n = 10), mental arithmetic (n = 12),
which include eight neurons tested in more than one task [Stroop + category + arithmetic (n = 1), Stroop + category
(n = 1), category + arithmetic (n = 4),
letters + arithmetic (n = 2)].
Neurons that were found to be modulated during performance of an
attention-demanding task were also tested for responses to painful
stimuli. These stimuli consisted of noxious mechanical (pin pricks) and
noxious thermal (hot, cold applied by a peltier-type thermode) stimuli
applied to the skin.
The approximate location of each neuron responsive to the
attention-demanding task(s) was reconstructed based on the landmarks identified on the patient's MRI (e.g., the size and shape of the ACC,
ventricles, anterior and posterior commissures, etc.) and stereotactic
coordinates of the electrode trajectory and recording site. These
landmarks allowed for an approximation of the anterior-posterior and
dorsoventral location of the recording site within the ACC. To
construct a composite map of sites across patients, a scaling factor
based on each subject's anterior commissure-posterior commissure (AC-PC) distance was used to correct for different brain sizes compared
with the 23 mm AC-PC line of the standard atlas. A standardized atlas
drawing of the ACC in sagittal plane (Talairach and Tournoux 1988
) was used to construct the composite of sites across all patients.
 |
RESULTS |
Of the 36 ACC neurons tested with the cognitive tasks, 7 neurons (19%) were clearly modified during one or more attention tasks. Neuronal activity was either enhanced (n = 4) or
attenuated (n = 3) during task performance (see Table
1). Three of these neurons were recorded during performance of two
tasks. There were no neurons whose activity was enhanced in one task
and inhibited during another task. Noxious stimuli had no effect on the
neuronal activity of the seven neurons modulated by the
attention-demanding tasks. The level of activity of the attenuated
neurons dropped to zero or near zero (1-2 Hz) during the task
performance from a baseline of 3-15 Hz. The activity of the enhanced
neurons increased two- to fivefold during the task, from 0-10 to
10-50 Hz. The baseline of each neuron was reasonably stable during
testing of each task. Figure 1 shows an
example of a neuron excited during mental arithmetic calculations. This
neuron had a very low level of tonic activity prior to and between
repetitions of the task. Figure 2 shows
an example of a neuron whose tonic neuronal activity was reduced during
two types of attention-demanding tasks: mental arithmetic and the
word-generation task. The neuronal activity of this neuron was
dramatically attenuated when the patient silently counted backward
(Fig. 2A) and completely ceased during the word-generation task (Fig. 2B).

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Fig. 1.
An excitatory effect of increased attentional demand in a single
neuron. This neuron had an excitatory response during performance of
mental arithmetic calculations. The patient (304) was
instructed to silently count backwards during the periods indicated by
the black bars. Each tick in the upper trace indicates the occurrence
of an action potential from 1 neuron extracted from the multi-unit
recording shown in the trace below.
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Fig. 2.
Inhibitory responses of a neuron during 2 different attention-demanding
tasks. The patient (351) was instructed to perform
mental arithmetic calculations (counting backward by 3, 5, or 7;
A) and silently generate words beginning with S, F, A,
or L (B). Task periods are indicated
( ).
|
|
The location of the attention-responsive neurons, reconstructed based
on stereotactic coordinates and each patient's MRI, are depicted in
Fig. 3. The data show an intermingling of
the neurons with inhibitory and excitatory responses regardless of laterality.

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Fig. 3.
Location of anterior cingulate cortex (ACC) neurons modulated during
performance of attention-demanding tasks. and and and , change in neuronal firing
during task performance as excitation or inhibition, respectively. The
shape of the symbols depict the laterality of each neuron
( and , left; and
, right ACC).
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 |
DISCUSSION |
This is the first report of single cortical neurons in the human
whose basal firing rate is modified by performance of cognitive tasks
that requires attention. The location of these neurons overlap the
region identified previously with functional MRI during similar attention-demanding word-generation tasks (Davis et al.
1997
). The lack of specificity to any one particular task
suggests that these neurons were responsive to some element inherent to
all tasks. However, it was surprising to find that the painful stimuli, which certainly tend to draw one's attention, did not alter the firing
rate of these neurons. Therefore these neurons are likely involved in
some more complex aspect of cognition or effortful thought rather than
simple attention. Although the exact function of these neurons require
further study, some possibilities can be drawn from their location
within the ACC, which has been implicated in a variety of cognitive
processes that require attention such as response selection, error
detection, and response competition (Carter et al. 1998
;
Devinsky et al. 1995
; Peterson et al.
1999
; Turken and Swick 1999
).
The findings indicate that cognitive neurons were located close
and slightly anterior to previously identified pain-related functional
MRI activations (Davis et al. 1997
) and pain-related ACC
neurons (Hutchison et al. 1999
). Although none of these
"attention cells" responded to painful stimuli, this does not rule
out the possibility that pain-responding cells are modulated by
attention since we did not subject all neurons to both attention and
painful stimuli. Therefore we cannot rule out the possibility that
pain-related responses are modified by attentional shifts. Indeed,
based on previous electrophysiological studies of central neurons in
monkeys (Bushnell and Duncan 1989
; Duncan et al.
1987
) and human pain perception (Bushnell et al.
1985
; Miron et al. 1989
), it is likely that
attention plays a significant role in shaping our appreciation of
external stimuli. Also interestingly, we previously reported possible
attentional effects on a pain-related ACC neuron (Hutchison et
al. 1999
). The neurons identified in the present study may provide one route whereby attention can influence perception of external stimuli. The attention-related increased or decreased background firing rates may act to set contrast levels for other possible inputs.
Inferences about the magnitude of the task effects are complicated by a
changing baseline of activity. The ongoing spontaneous activity is
likely affected by many cognitive factors as nebulous as what the
subject is "thinking." It is also possible that task difficulty has
an impact on modulation of spontaneous firing rate (Paus et al.
1998
). The patients in the present study were questioned after
the task to ensure that they were indeed engaged in the task. However,
in the future we plan to monitor and quantify task performance so that
task-related responses can be assessed in relation to the difficulty of
the task or its performance. The observation of both increases and
decreases in activity during task performance was not expected and is
open to interpretation. However, it suggests the neural circuitry
associated with such processes involves both excitatory and inhibitory
elements. This finding may impact on the interpretation of functional
imaging studies that typically identify "activations" assumed to
arise from increased synaptic activity.
In conclusion, the data indicate that there exists a subset of neurons
in the human ACC responsive to attention-demanding tasks that require
effortful thought but not to painful stimuli.
Address for reprint requests: K. D. Davis, Div. of Neurosurgery,
MP14-322, Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario
M5T 2S8, Canada.
The costs of publication of this article were defrayed in part
by the payment of page charges. The article must therefore be hereby
marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.