CORRESPONDENCE

Hypothalamic Oscillations in Human Pathological sive behavior (2–5). A further argument supporting a hypothalamic
Aggressiveness role in human aggressiveness comes from neurosurgery. For exam-
ple, lesions and deep brain stimulation (DBS) applied to the poste-
To the Editor: rior hypothalamus (pHyp) control aggressive behavior in humans
ny behavior intended to injure or harm another living being (6 –9). Despite evidence suggesting the hypothalamus as a pivotal

A (1) is defined as aggressive. Animal experiments showing

that electrical stimulation to the hypothalamus evokes ag-
gression suggest that this brain structure plays a key role in aggres-
structure in human aggressiveness, no research has investigated
intrinsic pathophysiologic abnormalities at hypothalamic level in
the neural network circuit mediating aggressiveness. Besides offer-

Figure 1. Comparison between aggressive patient (left) and control patient (right). (A) Preoperative magnetic resonance images fused with postoperative
computed tomographic slices to show the electrode position in the brain. Target coordinates, related to final position of macroelectrode contact 1, were
accorded to the anterior commissural–posterior commissural (AC–PC) line and midcommissural point (MCP); X, lateral from midline; Y, posterior from MCP; Z,
superior to AC–PC line. Note the macroelectrode tips in the posterior hypothalamus (pHyp) for the two patients (red arrows). (B) Top: pHyp local field potential
(LFP) 5 sec long, raw traces. Bottom: time-frequency plots for pHyp LFP power (1 min). Red represents the maximum power value for each plot. (C) pHyp LFP
power spectral density (PSD). Dashed horizontal lines represent thresholds for significant oscillations; arrows indicate significant power peaks. (D) Histograms
represent spectral power in the low-frequency (2–7 Hz), alpha (8 –12 Hz), low-beta (13–20 Hz), and high-beta (21–30 Hz) bands in the aggressive patient (black)
and in the control patient (gray). Error bars are standard deviation. ** p ⬍ .005. Note that in B, C, and D, LFPs in the aggressive patient have maximum power
in the low-frequency band (2–7 Hz), whereas LFPs in the control patient have highest power in the alpha band (8 –12 Hz).

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© 2012 Society of Biological Psychiatry
e34 BIOL PSYCHIATRY 2012;72:e33– e35
Table 1. Postoperative Follow-Up at 3 Months
Stimulation Frequency Pulse Width
Contacts (Hz)
Aggressive Patient (Case 1) Case(⫹) 2(⫺) 160
Control Patient (Case 2) Case(⫹) 2(⫺) 130
MOAS, Modified Overt Aggression Scale.
ing patients therapeutic benefits, DBS provides a unique opportu-
nity to record neural activity from human target structures. Local
field potentials (LFPs), the synchronous presynaptic and postsynap-
tic oscillatory activity in large neuronal populations, can be re-
corded after surgical positioning of the DBS electrodes in the target
structure (10). This experimental approach has already provided
physiological data on the physiology of the basal ganglia and other
subcortical structures in humans (11,12). To assess whether a spe-
cific neural hypothalamic activity pattern underlies pathological
human aggressiveness, we recorded and compared pHyp LFP in
two patients undergoing DBS: in one patient (case 1) to treat patho-
logic aggressiveness and in the other (case 2), a behaviorally normal
person considered as a control, to treat cluster headache (8). This
information, besides providing clues on the biological basis of ag-
gressiveness, might help improve DBS procedures to treat drug-
resistant aggressive behavior.
Case 1 is a 43-year-old man who manifested impulsive and ag-
gressive behavior against persons for 20 years. Sedative medica-
tions, including neuroleptics left his aggressiveness uncontrolled
and were interrupted owing to adverse effects such as motor insta-
bility and excessive sedation. Aggressive behavior was assessed
with the Modified Overt Aggression Scale (13). Case 2 is a 31-year-
old man who presented with drug-resistant chronic cluster left
headache. Despite receiving intramuscular injections and intrave-
nous morphine, he reported about 60 daily attacks. After informed
consent, both patients underwent a stereotactic macroelectrode
implant in the pHyp, bilateral in the aggressive patient and con-
tralateral to the pain in the control patient (right side), under gen-
eral anesthesia (propofol 1% 3– 4 mg/kg/h ⫹ remifentanil hydro-
chloride 0.1– 0.2 mg/kg/min). After DBS macroelectrode implant
(model 6145; St. Jude Medical, St. Paul, Minnesota), LFPs were re-
corded intraoperatively before macroelectrodes were connected to
the constant current pulse generator (Libra XP; St. Jude Medical).
LFPs were recorded from the right pHyp macroelectrode using a
bipolar configuration (14). Preoperative magnetic resonance im-
ages were fused with postoperative computed tomographic slices
to provide definitive target coordinates (Figure 1A). Both patients
were clinically evaluated at 3 months after DBS surgery to quantify
improvement. Data were analyzed offline with Matlab software
(version 7.10; The MathWorks, Natick, Massachusetts) first in the
time-frequency domain (15) and subsequently quantified in the
frequency domain by analyzing power spectral density (PSD) for
LFP recording time (60 sec) subdivided in consecutive 5-sec-long
segments (for details, see Rosa et al., 2011) (14). To evaluate pHyp
neurophysiological differences between the two patients, normal-
ized spectral power values (14) were compared for each band of
interest (low frequency: 2–7 Hz, alpha: 8 –12 Hz, low beta: 13–20 Hz,
high beta: 21–30 Hz) through a one-way analysis of variance (Statis-
tica 5.5; StatSoft Inc., Tulsa, Oklahoma) with factor “aggressive be-
www.sobp.org/journal
Correspondence
Current
(␮s) (mA) Clinical Improvement Drug Doses
90 1.9 Aggressive episodes Diminished to 50%
decreased by 70%. of the original
MOAS decreased from dose.
a preoperative
value of 17 to 7.
90 2 Attack numbers Morphine therapy
decreased by 80%. was withdrawn.
havior” (independent measures, 2 levels: presence, absence). p val-
ues ⱕ .05 were considered significant.
Visual inspection of the raw hypothalamic LFP recordings in
time domain (Figure 1B, top) and of the pHyp spectral power
in time-frequency plots (Figure 1B, bottom) showed that LFPs from
the pHyp differed between the aggressive patient and control pa-
tient. PSD for pHyp LFP recorded in the aggressive patient showed
a significant oscillation in the low-frequency band (spectral peak 2.6
Hz) with no activity in the alpha band (Figure 1C, left). Conversely, in
the control patient, a significant oscillation involved the alpha fre-
quency band (spectral peak 8.3 Hz) unaccompanied by activity in
the low-frequency band (Figure 1C, right). Spectral power in pHyp
LFP recordings differed significantly between the two patients.
Analysis of variance disclosed a significant effect of the factor “ag-
gressive behavior” for the low-frequency band (p ⬍ .005), alpha
band (p ⬍ .005), low-beta band (p ⬍ .005), and high-beta band (p ⬍
.005; Figure 1D). Postoperative follow-up at 3 months showed that
after DBS aggressive behavior decreased in case 1 and cluster head-
aches improved in case 2 (Table 1).
The first noteworthy finding in our study is that in the patient
with pathological aggressiveness, pHyp LFP showed increased low-
frequency oscillations and reduced alpha activity. Conversely, in
the behaviorally normal patient with cluster headache, they clearly
showed physiologic alpha hypothalamic activity (12), confirming
this patient as a valuable control. Because we used the same elec-
trode position and anaesthesia for DBS in both patients, we ensured
that neither factor influenced the different hypothalamic LFP
patterns recorded. The low-frequency power increase and alpha
power reduction we describe in pHyp LFP recordings in the aggres-
sive patient could be a specific pathologic marker for aggressive-
ness reflecting a dysfunction within the hypothalamic neural net-
work. DBS might have improved our patient’s aggressive behavior
by controlling the specific oscillatory activity in the pHyp. From a
practical point of view, the DBS-induced clinical improvement
shows that the electrode was properly placed in the effective DBS
target region for an aggressive syndrome. Hence, the LFP pattern
we found could help in neurophysiologic testing to identify the
target hypothalamic area during DBS surgery for aggressiveness.
Our findings can also be interpreted in a wider conceptual frame.
Emerging evidence shows that the low-frequency power increase
in basal ganglia LFP recorded from patients with Parkinson’s dis-
ease is related to impulsive behavior such as gambling (16) or
dyskinesias (17). The similar low-frequency power increase in our
aggressive patient and in those with Parkinson’s disease suggests
that, in the basal ganglia and in the pHyp, paroxysmal behavioral
manifestations varying in complexity (ranging from simple involun-
tary movements to complex structured behavior such as aggres-
sion or gambling) correlate with increased low-frequency oscilla-
Correspondence
tions that, in turn, could be the neurophysiologic correlate of
motor/behavioral disinhibition.
Manuela Rosaa
Angelo Franzinib
Gaia Giannicolaa
Giuseppe Messinab
Alfredo Carlo Altamurac,d
Alberto Prioria,d*
a
Centro Clinico per la Neurostimolazione, Le Neurotecnologie ed i Disordini del
Movimento, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.)
Ca’ Granda, Ospedale Maggiore Policlinico; bFondazione I.R.C.C.S. Istituto Nazionale
Neurologico Carlo Besta; cDipartimento di Salute Mentale Fondazione I.R.C.C.S.
Ca’ Granda, Ospedale Maggiore Policlinico; and dDipartimento di Fisiopatologia
Medico-Chirugica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.
*Corresponding author E-mail: alberto.priori@unimi.it.
This study was supported by the ERANET-Neuron Grant PhysiolDBS (Neuron-48-013),
by Fondazione I.R.C.C.S. Ca’ Granda Ospedale Maggiore Policlinico (Milan, Italy), Università
degli Studi di Milano (Italy), Ministero della Sanità (Italy), Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (Italy).
All authors report no biomedical financial interests or potential conflicts of
interest.
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http://dx.doi.org/10.1016/j.biopsych.2012.06.007
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