SPECT Findings in

Patients With
Primary Mania
Ricardo Migliorelli, M.D.
Sergio E. Starkstein, M.D., Ph.D.
Alejandra TesOn, Ph.D.
Guillermo de Quiros, M.D.
Silvia Vazquez, M.D.
RamOn Leiguarda, M.D.
Robert G. Robinson, M.D.

Five patients with a manic episode and 7 age- M ania is a well-known complication of brain lesions.’
We have recently reported on the clinical character-
corn parable control subjects were studied with
istics and correlates of mania in patients with cerebrovas-
single-photon emission computed tomography and
cular lesions, closed head injuries, or brain tumors.2
f 99mTcJd,l_hexamethylpro,leneamine oxime. Lesion side and location seem to be important factors in
Manic patients showed significantly lower blood the production of mania: manic patients were signifi-
flow in the basal portion of the right temporal lobe cantly more likely to have right as compared with left
compared with normal control subjects. Moreover, hemisphere lesions, and the lesions usually involved the
right basal frontal and temporal cortices (i.e., orbitofron-
manic patients showed a left-right asymmetry (a
tal and temporopolar), the right head of the caudate, and
significantly lower perfusion in the right versus
the right thalamus.1
left temporal basal cortex), as well as a dorsal- We have also carried out positron-emission tomogra-
vent ral asymmetry (a significantly lower perfu- phy (PET) scans using L’8F]fluorodeoxyglucose (18-FDG)
sion in the right temporal basal versus dorsal in 3 patients who developed mania after stroke or trau-
cortex). These findings suggest that the right matic lesions.5 Although the patients’ lesions involved
basotemporal cortex may play an important role the right head of the caudate and the anterior limb of the
internal capsule, all 3 patients showed a significant met-
in the production of primary mania.
abolic deficit involving the right basotemporal cortex
(The Journal of Neuropsychiatry and Clinical
(i.e., remote from the focal lesion), suggesting that dys-
Neurosciences 1993; 5:379-383)
function of this brain area may underlie the behavioral
changes in patients with secondary mania.
The aim of the present study was to investigate
whether patients with primary mania (i.e., mania with no
known brain injury) may also show blood flow abnor-

Received February 26, 1993; revised June 17, 1993; accepted June 24,
1993. From the Departments of Behavioral Neurology and Nuclear
Medicine, Ra#{252}lCarrea Institute of Neurological Research, Buenos Aires,
Argentina; and the Department of Psychiatry, University of Iowa
School of Medicine, Iowa City, Iowa. Address reprint requests to Dr.
Starkstein, Department of Behavioral Neurology, Instituto de In-
vestigaciones Neurol#{243}gicas “Ratil Carrea,” Ayacucho 2166, 1112
Buenos Aires, Argentina.
Copyright C) 1993 American Psychiatric Press, Inc.

JOURNAL OF NEUROPSYCHIATRY 379

SPECT FINDINGS IN PRIMARY MANIA

malities in similar brain regions. For this purpose, we planes obtained. Following the procedure of Burns et al.,7
examined a series of 5 patients with primary mania by square regions of interest (ROIs) of 4 x 4 pixels were used
using single-photon emission computed tomography to obtain activity ratios in axial slices, taking the cerebel-
(SPECT) and [Tc]d,1-hexamethylpropyleneamine lum as reference. Three measurements were carried out
oxime (HMPAO). These patients had no history of neuro- for each of the following cortical areas: inferior frontal,
logical disorders, showed no lesions on CT scan, and had temporal basal, temporal dorsal, and parietal. These mea-
not received psychotropic medication for at least 1 year. surements were averaged for each cortical region on the
right and left hemispheres. ROIs were also placed in the
basal ganglia, thalamus, and cerebellum. To determine
METHODS the activity ratio (brain region:cerebellum) the counts per
ROl of each cortical and subcortical area were divided by
Patients the counts per ROI found in the cerebellar hemisphere
The mania group included a consecutive series of 5 pa- that had the highest average count, and this ratio was
tients who were examined at the Department of Neuro-
psychiatry during a manic episode and met the following FIGURE 1. Top: Patient 1. Bottom: Patient 2. In each view, axial
inclusion criteria: 1) a manic episode based on DSM-III-R (upper left), sagittal (upper right), and coronal (lower
left) SPECT slices show decreased blood flow in the
criteria for mood disorder, manic episode; 2) no exposure right basotemporal lobe.
to psychoactive medication for at least 1 year; 3) no
history of neurological disorders; and 4) a normal CT
scan. The severity of manic symptoms was rated with the
Bech Mania Scale.6 None of the patients were taking
medications that could potentially cause mania (e.g., cor-
ticosteroids).
The control group included 7 right-handed age-
comparable individuals (5 normal control subjects and 2
patients who complained of dizziness and were referred
to the Department of Nuclear Medicine for a SPECT
scan). None of them had a positive history of psychiatric
disorders. All 7 individuals had a normal neurological
examination and a normal CT scan.

SPECT Study
After written consent was obtained from patients and
control subjects, a SPECT study was carried out. We used
[TcJHMPAO 25 mCi (Ceretec, Exametazime, Amer-
sham International, U.K.), which was injected intrave-
nously in an antecubital vein. Patients and control
subjects sat with eyes open and ears unplugged in a quiet
room with dim lights. Fifteen minutes after the injection,
patients were positioned supine and with the orbitomea-
tal line positioned vertically, centered in the field of view.
The alignment was carried out using vertical and hori-
zontal laser beams, and the head was held still by an ad
hoc head-holder. SPECT was carried out with a General
Electric 400 AC/T rotating gamma camera attached to a
Starcam 3200 computer.
We used a high-resolution collimator and a 64 x 64
matrix; 64 images were obtained over 360 degrees, with
an acquisition time of 30 s and a zoom of 1.6. Processing
was carried out with a Butterworth filtering, a critical
frequency of 0.44, and a slice width of 1 pixel. The data
were then filtered backprojected to obtain transaxial
slices, with subsequent reoriented coronal and sagittal

380 VOLUME 5 NUMBER

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 MIGLIORELLI et at.

used as a measure of regional cerebral blood flow (rCBF). There was

a left-right asymmetry for the temporal basal
All SPECT measurements were carried out by a neuro- cortex (right
< left, P = 0.004); as well as a dorsal-ventral
radiologist blind to the clinical data. asymmetry (basal <dorsal, P < 0.05; Figure 1). Moreover,
there was a nearly significant negative correlation be-
Statistical Analysis tween the Bech Mania Scale scores and right basotempo-
Statistical analysis was carried out using means and stan- ral blood flow (i.e., higher mania scores were correlated
dard deviations, analysis of variance with repeated mea- with significantly lower basotemporal blood flow) (r =
sures (ANOVA), and a Tukey post hoc test. All P-values -0.86, df = 4, P = 0.061).
are two-tailed. No other significant between-group differences were
found in the remaining brain areas. When the only male
control subject was excluded from statistical analysis,
RESULTS between-group differences in basotemporal blood flow
were still significant.
Demographic Data
The 5 patients with mania were right-handed females
with a mean age ± SD of 28±5.8 years and 10.6 ± 4.2 DISCUSSION
mean years of education. The mean Bech Mania Scale
score ± SD was 19.2 ± 7.7 (range 10-29 points). Two of the In the present study we compared 5 patients with an
patients had a history of short dysthymic periods, 2 affective disorder, manic episode, and 7 age-matched
patients had a history of manic-depressive cycles, and I control subjects for the presence of rCBF changes using
patient had no previous psychiatric history. All 5 patients HMPAO SPECT. There were two important findings.
had a positive history of psychiatric disorders in a first- First, manic patients showed a significantly lower CBF in
degree relative (4 bipolar manic and I schizoaffective). the right temporal basal cortex compared with normal
One manic patient received lithium for 5 months until I control subjects. Second, manic patients showed two sig-
year before the present manic episode. Another patient nificant asymmetries: a left-right asymmetry, which re-
had received imipramine and clomipramine for several sulted from a significantly lower blood flow in the right
years but had never received lithium or carbamazepine.
The other 3 patients had never received psychoactive TABLE 1. Regional cerebral blood flow measurements
drugs. Control subjects were 6 females and I male and Region/cerebellum (mean ± SD)
had a mean age of 25.2 ± 10.1 years. Control Group Mania Group
BrainArea (n=7) (n=5)
SPECT Findings
Frontal inferior
Table I shows rCBF for the regions studied. A 3-way Left 81.2± 7.2 82.0 ± 10.6
analysis of variance (ANOVA) showed no significant Right 81.1 ±7.6 81.8 ± 7.4
group effect, no significant group x region interaction, Temporal dorsal
and no significant group x side interaction, but a signifi- Left 90.5±4.1 87.6 ± 6.6
Righta 91 .4 ± 5.8 87.8 ± 2.6
cant group x side x region interaction (F = 2.70, df = 5,50,
Temporal basal
P = 0.030). This triple interaction was the result of a sig-
Leftb 92.2±4.6 91 .4 ± 6.5
nificantly lower CBF of the right basotemporal cortex in Righta 90.8 ± 4.7 79.6±5.0
manic patients compared with normal control subjects Parietal
(Tukey, P = 0.0002). To further explore the presence of Left 94.1 ±5.6 92.0 ± 3.5
left-right and dorsal-ventral asymmetries in temporal Right 92.2 ± 5.4 88.8±3.9
Basal ganglia
lobe blood flow, we carried out a 3-way ANOVA with
Left 92.8 ± 7.1 91 .0 ± 4.7
repeated measures with temporal basal and temporal
Right 93.0 ± 7.1 92.0 ± 5.2
dorsal blood flow as the region variable. There was a Thalamus
significant group effect (manic patients had significantly Left 85.5±7.0 91.4 ± 2.5
lower overall temporal blood flow; F = 5.26, df = 1,10, Right 85.7±7.3 86.0±4.8

P < 0.05) and a significant group x region x side interac- aRight temporal basal, manic patients, vs. right temporal dorsal,
tion (F = 5.93, df = 1,10, P = 0.035). This triple interaction manic patients, 3-way analysis of variance, P < 0.05.
bRight vs left temporal basal, manic patients, Tukey’s post hoc test,
resulted from the expected lower blood flow in the tem-
poral basal cortex of manic patients compared with nor- P = 0.004.
cRight temporal basal, manic patients vs. control subjects, 3-way
mal control subjects (P = 0.006), as well as from analysis of variance, P = 0.0002.
significant CBF differences within the mania group.

JOURNAL OF NEUROPSYCHIATRY 381

SPECT FINDINGS IN PRIMARY MANIA

versus left temporal basal area, and a ventral-dorsal den for psychiatric disorders, right basotemporal dys-
asymmetry, which resulted from a significantly lower function may be associated with mania in patients with
basal versus dorsal right temporal blood flow. or without brain lesions.
Before further discussing these findings, we should The basotemporal cortex is a paralimbic area with im-
point out some limitations of our study. First, we in- portant afferents from secondary sensory (frontal, dorsal
cluded only 5 patients with mania, and our results should temporal, and parietal), limbic (through the orbitofrontal
be considered preliminary. Second, we did not repeat the cortex and the uncinate fasciculus), and paralimbic areas
SPECT scan after the pharmacological treatment of the (such as the insular cortex and the parahippocampal
manic episode, so we could not determine whether the gyrus).1#{176}Based on these inputs, the basotemporal cortex
CBF changes in our manic patients were state -or trait- may serve a function to generate a “context” that influ-
related. Third, all our manic patients were females, and ences the likelihood of a specific behavior’s taking place
whether our present findings are gender-specific will (i.e., whether that specific behavior is released or inhib-
have to be examined in future studies. ited). Thus, dysfunction of this area may result in motor
Few studies have examined blood flow or metabolic disinhibition (e.g., hyperactivity and pressured speech),
changes in patients with primary mama. Baxter et al.8 intellectual disinhibition, (e.g., flight of ideas and grandi-
carried out 18-FDG PET scans in 5 bipolar patients in a ose delusions), and instinctive disinhibition (e.g., hyper-
manic phase who were drug free for at least I week. sexuality and orality).
Whole brain or regional metabolic rates did not differ Additional support for the role of the right basotempo-
significantly between manic patients and control sub- ral cortex in the production of mania may be found in the
jects. Our sample was different from that of Baxter et al. epilepsy literature. Barczak et al.’1 reported 3 patients
in that 3 of our 5 patients were examined at the time of with right side temporal lobe epilepsy who became hy-
their initial manic episode, and none of our patients pomanic following an increase in the frequency of the
received psychotropic medication for at least 1 year. seizures. Drake’2 reported the case of an epileptic patient
Silfverskj#{246}ld and Risberg9 carried out rCBF studies with with a bipolar disease who had a normal EEC while
xenon-133 in 30 patients who were experiencing a manic euthymic, had a focal slowing in the left temporal region
episode. They found a significantly lower CBF in female while depressed, and had a right temporal slowing dur-
(but not male) manic patients as compared with control ing periods of hypomanic behavior. Moreover, Gillig et
subjects. However, at the time of the examination, most al.’3 have recently reported a patient with continuous
patients were on neuroleptics or other psychopharmaco- nonrhythmic slowing in the right parietal and right pos-
logical drugs, and there was a negative relationship be- terior temporal areas who showed manic behavior dur-
tween rCBF and neuroleptic medication type and dosage. ing the period of EEC changes.
The finding in our study of a significantly decreased The second important finding of this study was the
right temporal basal blood flow in manic patients with significant lateralization of the CBF change; patients with
no known brain lesions is similar to our previous report primary mania showed basotemporal perfusion deficits
of significantly reduced metabolic activity in the same restricted to the right hemisphere. In an animal model of
brain area in patients who developed mania after isch- affective disorders we demonstrated that focal lesions of
emic lesions of the right head of the caudate and the the right (but not left) hemisphere produced locomotor
anterior limb of the internal capsule.5 Although our hyperactivity.’4 This right-hemisphere-induced locomo-
SPECT and PET studies are not directly comparable be- tor hyperactivity was present after either frontal cortical
cause the former measured CBF whereas the latter mea- lesions or subcortical lesions in the nucleus accumbens
sured metabolic activity, our findings suggest that (NA). Moreover, we have recently produced locomotor
primary and secondary mania may share dysfunction in hyperactivity in rhesus monkeys after small right (but
a similar brain area. This dysfunction may not be age not left) caudate lesions)5 We also found that right (but
related; the mean age in our primary mania group was not left) cortical lesions produced significant increments
28 years, whereas the mean age in our previously re- in the dopaminergic turnover in the NA, and there was
ported secondary mania group was 57 years.5 Moreover, a significant positive correlation between the magnitude
this localized brain dysfunction was present in manic of DA turnover in the NA and the degree of hyperactiv-
patients with and without a genetic burden for psychiat- ity.14 Thus, it is possible that the underlying mechanism
ric disorders; all our 5 patients with primary mania had of mania may not only require dysfunction of limbic-
a positive family history of psychiatric disorders in a related regions, but lateralized changes in biogenic amine
first-degree relative, as compared with none of our 3 pathways as well.
patients with secondary mania in our previous report. In summary, we have demonstrated changes in blood
Thus, regardless of age or the presence of a genetic bur- flow in the right basotemporal cortex in patients with

382 VOLUME 5 NUMBER

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 MIGLIORELLI et a!.

primary mania. The changes are similar to those we The authors thank Dr. Juan Carlos Goldar for his most valuable
found in patients with mania after brain lesions. These suggestions.
results suggest that the right basotemporal cortex may This study was partially supported by grants from the
constitute an important common pathway in the produc- Instituto Di Tella, the Sandoz Foundation, and the National
tion of mania. Institutes of Health (ROl MI-140355).

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JOURNAL OF NEUROPSYCHIATRY 383