J. Sleep Res.

(2012) 21, 502–506 Local sleep and parasomnia

Dissociated local arousal states underlying essential clinical

features of non-rapid eye movement arousal parasomnia:
an intracerebral stereo-electroencephalographic study
MICHELE TERZAGHI1, IVANA SARTORI2, LAURA TASSI2,
VALTER RUSTIONI1, PAOLA PROSERPIO2, GIORGIO LORUSSO2,
R A F F A E L E M A N N I 1 and L I N O N O B I L I 2
1
Sleep Medicine and Epilepsy Unit, IRCCS National Neurological Institute C. Mondino Foundation, Pavia, Italy and 2Epilepsy Surgery Centre
ÔC. MunariÕ, Sleep Disorder Centre, Niguarda Hospital, Milan, Italy

Keywords
confusional arousal, local arousal, NREM
parasomnia, state dissociation, stereo-EEG
Correspondence
Michele Terzaghi MD, Sleep Medicine and
Epilepsy Unit, IRCCS National Neurological
Institute C. Mondino Foundation, Via Mondino 2,
27100 Pavia, Italy.
Tel.: +390382380316;
fax: +390382380286;
e-mail: michele.terzaghi@mondino.it
Accepted in revised form 14 January 2012;
received 21 September 2011
SUMMARY
Sleep has been shown to be a global phenomenon in which the presence
of local processes of both activation and deactivation are finely
orchestrated. Dysfunctional and independent action of the systems
involved in non-rapid eye movement (NREM) sleep and wakefulness is
deemed to be at the basis of arousal parasomnias. We show, in a patient
with confusional arousals, persistence of sleep in the hippocampal and
frontal associative cortices in contrast to the presence of awakening in
the motor, cingulate, insular, amygdalar and temporopolar cortices. The
clinical features of the confusional arousals in this patient are highly
consistent with a dysfunctional coexistence of local cortical arousal and
local cortical sleep.

DOI: 10.1111/j.1365-2869.2012.01003.x

INTRODUCTION SUBJECTS AND METHODS

Whole-organism sleep can be viewed as a global pheno-
menon based on the presence of finely orchestrated local
processes of both activation and deactivation (Nir et al.,
2011; Nobili et al., 2011), and underpinned by local neuronal
networks (Krueger et al., 2008). Dysfunctional and indepen-
dent action of the systems involved in non-rapid eye
movement (NREM) sleep and wakefulness is deemed to
be at the basis of arousal parasomnias (Mahowald and
Schenck, 2005).
By deep brain neurophysiologic study we demonstrated
the presence of local sleep during episodes of confusional
arousal (Terzaghi et al., 2009); local sleep has also been
documented in sleepwalking by single photon emission
computed tomography (Bassetti et al., 2000).
We report data from an intracerebral electroencephalo-
graphic (stereo-EEG, S-EEG) study that captured confu-
sional arousals in a young boy. The data document the
persistence of delta activity in the hippocampal and frontal
associative cortices, in contrast to the presence of a local
activation of the motor, cingulate, insular and temporopolar
cortices and amygdala.
A 7-year-old boy was admitted to the ÔC. MunariÕ Epilepsy
and ParkinsonÕs Disease Surgery Centre, Niguarda Hospital,
Milan, for presurgical evaluation of nocturnal episodes
consisting of awakenings accompanied by slow or agitated
movements of the arms and legs, scratching of the nose,
blinking and looking around; the patient would turn
over, get onto his knees or sit up in bed, sometimes
abruptly, would not answer his parents trying unsuccess-
fully to wake him, and might display signs of hunger or
fear. Lucid recall was absent on awakening. These
episodes had begun when the child was 3 years old.
Lasting for seconds or a few minutes, they occurred
weekly or less frequently.
The patientÕs family history was negative for arousal
parasomnias. Neurological examination was unremark-
able; magnetic resonance imaging (MRI) gave normal
findings.
Different anti-epileptic agents, in monotherapy or polyther-
apy, had been administered; no drug regimen had been
found to improve the symptoms [the patient was still on anti-
epilectic drugs (AEDs)].

502 ª 2012 European Sleep Research Society


Figure 1. Stereo-electroencephalogram (stereo-EEG) exploration: medial and lateral views of the stereotactic electrode implantation.
Neurophysiological study
After informed consent had been obtained, the patient was
submitted to a tailored investigation using intracerebral
implanted electrodes to search an epileptogenic area.
On the basis of anatomo-electroclinical data, 13 stereo-
tactically implanted intracerebral multi-lead electrodes (Dixi
Medical, Besançon, France) were placed in the fronto–
centro–temporal areas of the right hemisphere: in the primary
sensory motor cortex (central and postcentral gyrus), supe-
rior, middle and inferior frontal gyrus, supplementary sensory
motor area, superior and middle temporal gyrus, frontal and
central cingulate gyrus, short and long gyri of the insula,
hippocampus and amygdala (Fig. 1). The placement of the
intracerebral leads was checked by MRI. For sleep staging
(Fig. 2), electro-oculogram and submental electromyography
(EMG) were recorded.
RESULTS
The S-EEG shows background activity with physiological
phasic sleep events appearing both synchronously and
asynchronously in different brain regions. In particular, while
hippocampal and neocortical spindles remain asynchronous
throughout the night, asynchronous spindles in the neocor-
tical areas showed a trend to occur slightly more frequently
during the second half of the night (Fig. 3).
The S-EEG trace showed the possible occurrence of
transient and abrupt shift to sustained fast activity in the
motor, cingulate (frontal and central cingulate gyrus), insular,
temporopolar and amygdalar cortices in contrast to the
presence of slow waves in the frontal and parietal dorsolat-
eral cortices as well as persistent spindles in the hippocam-
Figure 2. Hypnogram and macrostructural sleep scoring data.
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Local sleep and NREM parasomnia 503
pal cortex. This localized arousal activity could occur in
absence of any detectable clinical manifestation (Fig. 4a).
During motor behavioural manifestations consistent with
the anamnestic report (sitting up, looking around), the S-EEG
trace showed a more pronounced localized arousal activity
(Fig. 4b). No interictal or ictal epileptiform abnormalities could
be found.
Clinical and S-EEG findings allowed us to rule out a
diagnosis of epilepsy, the data pointing instead to a diagnosis
of arousal disorder. Treatment with AEDs was stopped
completely. Modification of sleep hygiene and melatonin
3 mg at bedtime led to a clear improvement of the sleep-
related manifestations.
DISCUSSION
It has been shown that both active and inactive neuronal
states can occur locally during sleep (Nir et al., 2011), and
some brain networks can exhibit sleep patterns while others
exhibit wake-like activities (Nobili et al., 2011; Terzaghi et al.,
2009).
During an episode of confusional arousal, we found that
the motor and cingulate cortices were precociously activated
(probably allowing motor output), while the frontoparietal
associative cortices continued to maintain a sleep pattern
(Terzaghi et al., 2009).
In the patient described in this study, the data obtained
confirmed the presence of dissociated activations and sleep-
like electrocortical activity in these different brain regions.
Moreover, the presence of arousal activity was also found in
the insular, temporopolar and amygdalar cortices, while the
hippocampal cortex showed the persistence of a sleep-like
pattern.
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504 M. Terzaghi et al.

(a) SSMA
Motor
Cortex

Cingulate
Cortex

Temporal
Pole
Insular
Cortex
Amygdalar
Cortex

Frontal
Associative
Areas

Hyppocampus

(b) SSMA
Motor
Cortex

Cingulate
Cortex

Temporal
Pole
Insular
Cortex
Amygdalar
Cortex

Frontal
Associative
Areas

Hyppocampus

(c)
SSMA
Motor
Cortex

Cingulate
Cortex

Temporal
Pole
Insular
Cortex
Amygdalar
Cortex

Frontal
Associative
Areas

Hyppocampus

Figure 3. Stereo-electroencephalogram (stereo-EEG)-captured activity: absence of epileptiform abnormalities in the presence of normal phasic
events of sleep (spindle activity) appearing synchronously and asynchronously in the different brain regions explored. Each image was taken
during undisturbed sleep i.e. preceding or following by at least 15 minutes a pathological arousal clinical manifestation. (a) Descending slope of
the first sleep cycle, Stage 2 non-rapid eye movement (NREM), 35 min after sleep onset. (b) Ascending slope of the first sleep cycle, Stage 2
NREM, 155 min after sleep onset. (c) Ascending slope of the third sleep cycle, Stage 2 NREM, 350 min after sleep onset. Note that phasic
events expressed less asynchronously at the beginning of the night (with high homeostatic pressure) and mainly over the hippocampal leads
(largely independent from frontocentral cortices). Each EEG trace is a bipolar derivation from contiguous contacts. Six derivations record from
the frontal dorsolateral associative cortex (H10–H11, H15–H16, F12–F13 and F13–F14: middle frontal gyrus; G13–G14 and F1–F2: superior
frontal gyrus); three from the hippocampus (B2–B3; B3–B4; B4–B5, note the persistence of spindle activity); one from the temporal pole (T3–
T4); one from the insular cortex (R1–R2); two from the amygdala (A1–A2; A2–A3); seven from the motor and motor control cortex (M1–M2:
supplementary sensory motor area; M6–M7: precentral gyrus; S12–S13:primary motor area; G1–G2: anterior cingulate gyrus; H1–H2 and H2–
H3: frontal cingulate gyrus; S1–S2: central cingulate gyrus). EOG: electro-oculogram; Chin: chin electromyography; EKG: electrocardiogram.

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Local sleep and NREM parasomnia 505

(a)

(b)

(c)

Figure 4. Local dissociation of sleep and arousal captured by stereo-electroencephalogram (stereo-EEG). (a) Example of local activation in the
motor, cingulate (frontal and central cingulate gyrus), insular, temporopolar and amygdalar cortices in contrast to the presence of slow waves in
the frontal and parietal dorsolateral cortices as well as persistent spindles in the hippocampal cortex. (b) Arousal local dissociation captured by
stereo-EEG in relation to clinical manifestations: a 30-s episode during which, with his eyes open, the patient sat up in bed, uttering unintelligible
words and failing to answer his motherÕs questions. (c) Undisturbed sleep taken during the same time of the night (for comparison of EEG traces
between local arousal event and normal sleep). Each EEG trace is a bipolar derivation from contiguous contacts. Six derivations record from the
frontal dorsolateral associative cortex (H10–H11, H15–H16, F12–F13 and F13–F14: middle frontal gyrus; G13–G14 and F1–F2: superior frontal
gyrus); three from the hippocampus (B2–B3; B3–B4; B4–B5: note the persistence of spindle activity); one from the temporal pole (T3–T4); one
from the insular cortex (R1–R2); two from the amygdala (A1–A2; A2–A3); seven from the motor and motor control cortex (M1–M2: supple-
mentary sensory motor area; M6–M7: precentral gyrus; S12– S13: primary motor area; G1–G2: anterior cingulate gyrus; H1–H2 and H2–H3:
frontal cingulate gyrus; S1–S2: central cingulate gyrus). EOG: electro-oculogram; Chin: chin electromyography; EKG: electrocardiogram.

ª 2012 European Sleep Research Society


506 M. Terzaghi et al.
Recently, a study adopting intracerebral unit firing record-
ings in humans have shown that most sleep spindles and
slow waves occur locally; in particular, in late sleep when the
homeostatic pressure is lower, some regions could be active
while others are silent (Nir et al., 2011). Furthermore, it has
been observed that local cortical activations are an intrinsic
feature of physiological NREM sleep and are probably
modulated by a homeostatic process, as their number
increases progressively across sleep cycles paralleling the
decrease of slow wave activity (SWA) (Nobili et al., 2011).
Consistently, our observation of asynchronous sleep spindles
and the presence of local cortical activations in the absence
of motor behaviours confirm further that sleep is not a spatial
and temporal global uniform state.
Although we did not study in detail the dynamics of SWA
and the distribution of local activation, the observation that
asynchronous sleep events show a trend to occur slightly
more frequently during the second half of the night points to a
possible analogous homeostatic control.
A hierarchical different threshold of arousability between
different cortical areas (namely the motor ⁄ cingulate, insular
and amygdalar cortices would be more prone to be activated)
could be hypothesized to be possibly related to an adaptive
behaviour (Nobili et al., 2011).
From a clinical perspective, a dysfunctional co-existence of
activation ⁄ deactivation processes may help to explain the
clinical findings of dissociated arousal events (Mahowald and
Schenck, 2005).
The amygdala, a centre of emotions and instinctive
behaviour (LeDoux, 1992), has complex anatomical and
functional connections with the prefrontal cortices (Salzman
and Fusi, 2010; Sotres-Bayon and Quirk, 2010) with the
insular regions (Augustine, 1996) and the temporal pole,
which has been implicated in cognitive processes associated
with emotions (Dolan et al., 2000; Pelletier et al., 2003).
The hippocampus, medial temporal lobes and neocortex,
especially the prefrontal and parietal regions (Buckner et al.,
2008; Moscovitch, 1995; Nordahl et al., 2006), are involved in
complex networks supporting episodic memory and con-
scious recall (Ranganath, 2010).
Thus, from a speculative perspective, typical features of
arousal parasomnias could be explained by the activation of
the amygdalo–temporo–insular areas disengaged from the
prefrontal control cortex (emotional activation, such as fear),
paralleled by the deactivation of the hippocampal and frontal
associative cortices (amnesia for the event).
Finally, from a clinical perspective, it must be recalled that
short-lasting ÔminorÕ motor events, even highly stereotyped
ones such as those captured in the subject described in this
study, can occur in the absence of an epileptiform discharge
(Terzaghi et al., 2007), and arousal fluctuation per se (Nobili
et al., 2006; Parrino et al., 2006; Terzaghi et al., 2008) has
been reported to be a common denominator of these motor
manifestations, which may be considered to arise from
aspecific arousal-related motor dishinibition rather than being
epileptic in origin.
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CONFLICTS OF INTEREST
The authors report no conflicts of interest.
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