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Mania atter Bran Injury: Neuroradiological
and Metabolic Findings
Sergio E. Starkstein, MD,"n Helen S. Mayberg, MD,I$ Marcelo L. Berthier, MD,"" Paul Fedoroff, MD,"
Thomas R. Price, MD,?? Robert F. Dannals, PhD,S Henry N. Wagner, MD,$ Ramon Leiguarda, MD,""
and Robert G. Robinson, MD"§
We present a consecutive series of 8 patients who developed a manic episode after a brain injury. Five patients had
cortical lesions (4 with damage to the right basotemporal region, and 1with bilateral damage to the orbitofrontal area).
While the other 3 patients had subcortical lesions (white matter of the right frontal lobe, right anterior limb of the
internal capsule, and right head of the caudate), a %uorodeoxyglucose positron emission tomography scan showed
hypometabolism in the right lateral basotemporal region in all 3 patients. These findings suggest a major role for the
basal region of the right temporal lobe in the modulation of mood.

-

Starkstein SE, Mayberg HS, Berthier ML, Fedoroff P, Price TR,Dannals RF,Wagner HN,
Leiguarda R, Robinson RG. Mania after brain injury: neuroradiological
and metabolic findings. Ann Neurol 1990;27:652-659

Although secondary mania (mania after a brain injury)
is relatively rare, recent studies suggested an important
role of lesion location in the production of this disorder {l]. In a series of 12 patients with secondary
mania, we reported a high frequency of lesions in the
right hemisphere, which primarily involved limbic or
limbic-related cortical (orbitofrontal or basotemporal)
or subcortical (caudate nucleus or thalamus) regions {2,
51.

In the present study, we examined a new independent series of 8 patients with secondary mania. We
report here on neuroradiological findings and focal
metabolic abnormalities distant from the site of lesion,
which may be specific to secondary mania.

Material and Methods
Patients
A consecutive series of patients admitted to the Department
of Neurology (Stroke Unit) of the University of Maryland
Hospital (Baltimore, MD), the Phipps Clinic at Johns Hopkins Hospital (Baltimore, MD), and the Institute of Neurological Research (Buenos Aires, Argentina), with a diagnosis
of both mania and a brain lesion during the period between
October 1986 to October 1988, were included in the study.

Psychiatric Evaluation
The psychiatric evaluation consisted of a modified version of
the Present State Exam [4] (a semistructured psychiatric in-

From the Departments of *Psychiatry and Behavioral Science,
?Neurology, $Nuclear Medicine, and §Neurosciences,Johns Hopkins University School of Medicine, Baltimore, MD, the "University
of Buenos Aires and the **Institute of Neurological Research "Dr
Raul Carrea," Buenos Aires, Argentina; and the ttDepartment of
Neurology, University of Maryland School of Medicine, Baltimore,
MD.

terview that elicits symptoms related to depression, anxiety,
and mania) and a mania rating scale [ S ] . Secondary mania was
diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) (DSM-111-R) [6] criteria for an
organic affective disorder, manic type, as well as the more
stringent criteria for a major affective disorder, manic episode. Handedness was assessed with the Edinburgh Handedness Inventory [7}.

PET Scan Methodology
After giving informed consent, patients underwent 18fluorodeoxyglucose positron emission tomography (l8FDG PET)
as follows [8]: a computed tomography (CT) scan was obtained using an imaging plane parallel to the glabellarinion line, which passed symmetrically through the area of
lesion documented by CT or magnetic resonance imaging
(MRI) evaluation. An alignment line was drawn on a thermoplastic, individually fitted mask, which was subsequently used
to establish the 12 imaging planes in the "FDG PET study.
18FDG was injected while the patient was awake in a quiet
room but with eyes closed. The scanning procedure began
45 minutes after the radiotracer was injected. Twelve contiguous slices incorporating the full rostral-caudal extent of
the brain were obtained. Images were acquired in the highresolution mode (slice thickness: 14.5 mm; in-plane resolution: 8 mm). Data were corrected for attenuation and
radioactive decay. Absolute metabolic rates for glucose
(CMRGlc) were calculated using previously described
methods 19, lo]. The whole brain metabolic rate was cal-

Received Aug 21, 1989, and in revised form Nov 14. Accepted for
publication Dec 13, 1989.
Address correspondence

D~ Starkstein, D~~~~~~~ of psychia-

try, M~~~~4-119,~ohns~~~k~~
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~ i N,~ wolfe
a l st,
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more, MD 21205,

652 Copyright 0 1990 by the American Neurological Association

culated by averaging the CMRGlc of cortical and subcortical
regions from multiple slices (approximately 70 regions of
equal size in each hemisphere). Regions of interest (ROIs)
were drawn in symmetrical left and right cortical areas, remote from the documented site of lesion (e.g., there were 14
ROIs distributed within the inferior temporal area of the
cortex spanning the whole anterior-posterior extent of the
temporal lobe). An Asymmetry Index (AI) ({right - left/
right + left) x 200) was calculated { 111.
Three normal control subjects (age range, 35 to 45 years)
were also scanned. None of them had neurological or psychiatric disorders, and none of them were taking medications at
the time of the PET scan.

Results
Clinical Findings
Mean age (years
SD) was 49 & 17 (range, 25-79 years). Seven
patients were men, and 7 were right-handed. Only 1
patient (Patient 6) had a family history of psychiatric
disorder (affective disorder in a first-degree relative),
and none had a personal history of psychiatric disorder. The interval between the time the lesion occurred
and the onset of manic symptoms was immediate in 5
patients, and 2, 6, and 24 months in the other 3 patients.
BACKGROUND CHARACTERISTICS.
&

All patients had mania scale
scores in the manic range (mean points
SD: 22.7 &
6.1; range: 15 to 33 points). All 8 patients were elated,
and had pressured speech and grandiose delusions.
Seven were hyperactive and had flight of ideas and
insomnia; 6 were hypersexual and overspent money,
and 5 were irritable. Mean Mini-Mental State Exam
(MMSE) {12) scores were (mean 2 SD) 28.1 & 3.5.
Only 1 patient had a MMSE score below 24.
PSYCHIATRIC FINDINGS.

*

Case Reports
The cases of the 3 patients who had an "FDG-PET
scan are briefly described below.
PATIENT 1. A 37-year-old white man had a closed head
injury in December 1986 (he was hit by a piece of metal
after a gas tank exploded). H e remained unconscious for
several hours, was later disoriented for place and time, but
showed no focal signs on neurological examination. A CT
scan showed a small hemorrhagic contusion in the white
matter of the right frontal lobe.
During the next 6 days he became increasingly hyperactive, demonstrating grandiose delusions (e.g., he said he
would mediate in a foreign war), felt full of energy, and
believed that his health was better than ever. He only slept 2
hours a night, and showed pressured speech and mild irritability. After hospital discharge, he began to overspend (e.g.,
he went to an auto dealer and tried to buy an expensive new
car, for which he offered twice the asking price).
In September 1987, the patient was started on lithium
therapy, 500 mgday, with no improvement in his manic
symptoms. In October 1987 he was hospitalized, the lithium

Fig 1. Patient 1. T2-weightedMRI scan showing a small lucency in thefrontal white matter of the right hemisphere
(arrow).
dosage was increased to 1,000 mglday, and treatment with
fluphenazine, 2.5 mglday, was started. Two weeks later,
while he was taking only lithium (1,200 mglday), a "FDG
PET scan was performed. An MRI scan showed a small lucency in the location of the original right frontal contusion
(Fig l), and a small pseudoporencephalic cyst in the left
temporal lobe. At the time of PET scan, his mental status
exam revealed an elevated mood, grandiosity, pressured
speech, increased energy, poor insight, and irritability. His
mania scale score was 15 points.
PATIENT 2. In November 1986, a 55-year-old man had a
brief episode of dysarthria. Several days later, he became
extremely depressed and had decreased appetite, as well as
initial and terminal insomnia, loss of interest in his usual
activities, and loss of libido. Four weeks later he became
hyperactive and euphoric and showed decreased need for
sleep, as well as pressured speech and grandiose ideation.
Although he was started on treatment with haloperidol, his
manic symptoms became increasingly severe and he required
hospital admission. Ten days after lithium therapy was
started (500 mglday), the manic symptoms became less severe. Two weeks later, the patient was discharged from the
hospital but lithium had to be discontinued because of side
effects. In April 1987, the patient was drug-free, and MRI
and PET studies were performed. The MRI scan showed an
ischemic infarction involving the anterior limb of the right
internal capsule and the inferior portion of the head of the
caudate (Fig 2). At the time of the scans, the patient's mental
status exam showed an elevated mood, grandiosity, pressured speech, and easy distractibility. H e stated that his sex
drive was better than before the stroke, and that he had
decreased need for sleep. His mania scale score was 21
points.

Starkstein et al: Secondary Mania 653

Fig 2. Patient 2. MRI scan showing an ischemic infarction involving the ventralpart of the right internal capsule (small arrow), and partially, the outer third of the right head of the
caadute (large arrow).

Fig 3. Patient 3. CT scan showing an ischemic infarction involving the right head of the caudate and the anterior limb of
the internal capsule (arrowhead).

PATIENT 3.

A 79-year-old woman had gone on an overseas
trip, and during the second week her roommates reported a
sudden change in her behavior. She did not sleep at night,
was very hyperactive, and had an elevated mood. She began
to write incessantly, but her writings were impossible to
understand. She believed that foreign spies were watching
her, and on one occasion she called the police to protect her.
After returning to the United States, she was found by her
relatives, wandering and confused in the airport.
O n hospital admission, findings o n neurological examination were normal. Toxicology screen; complete blood cell
count; VDRL result; and triiodothyronine, thyroxine, and
vitamin B12 determinations were all within normal limits. A
C T scan (Fig 3) showed an ischemic infarction involving the
right head of the caudate and extending into the anterior
limb of the internal capsule. During the hospitalization, the
manic behavior was characterized by elation, hyperactivity,
flight of ideas, insomnia, grandiose delusions, hypersexuality,
and pressured speech. She was started on treatment with
lithium, 300 mglday, showed a gradual recovery, and was
discharged 4 weeks later.
Lithium was discontinued in March 1988, but 6 months
later, the patient had a second manic episode and had to be
readmitted to hospital. A new C T scan only showed the
original right caudate lesion, and a "FDG PET scan was
performed. At that time, her mental status exam revealed an
elevated mood, pressured speech, flight of ideas, and hypersexuality. She also had insomnia and showed moderate
hyperactivity. H e r mania scale score was 33 points. At the
time of PET scan she was taking lithium (500 mglday) and no
other medication.

654 Annals of Neurology Vol 27 No 6 June 1990

Neurorudiologicul Findings
Five of the 8 patients had cortical lesions. One patient
(Patient 4 ) had a right ischemic infarction involving the
basotemporal region of the cortex (Fig 4A), and the
medial temporal gyms, dorsolateral frontal area of the
cortex, and head of the caudate (Fig 4B).Another
patient (Patient 5) had a right ischemic infarction involving the basotemporal area of the cortex, the amygdala, the hippocampus (Fig 5A),and the head of the
caudate (Fig 5B).A third patient (Patient 6) developed
mania immediately after a therapeutic embolitation of
a right basotemporal arteriovenous malformation; this
case is reviewed elsewhere C131. An MRI showed an
arteriovenous malformation involving the basal region
of the right temporal lobe (Fig 6). One patient (Patient
7) (Fig 7) had a hemorrhage involving the basal area of
the right temporal lobe. One patient (Patient 8) (Fig 8)
had bilateral orbitofrontal contusions. Three patients
(Patients 1 to 3 ) (already described) had subcortical
lesions in the right hemisphere.
Metabolic Findings
Assessment of metabolic activity for individual patients within relevant brain regions (lateral temporal,
inferior frontal, superior frontal, and parietal regions)
showed a significant asymmetry (right side < left side)

Fig 4. Patient 4. C T scan showing a right ischemic infarction
involving the basotemporal region ofthe cortex (A), and the medial temporal gyrus, dorsolateralfrontal area of the cortex, and
head of the caudate (B).

Fig 5 . Patient 5. inverted T2-weighted MRI scan shwuing an
ischemic infarction involving the basal (arrows) and medial
areas of the right temporal lobe (arrowhead) (A) and the head
of the caudate (B).

Starkstein et al: Secondary Mania

655

Fig 6. Patient 6. Inverted T2-weighted axial MRI scan showing an arteriovenous malfarmation involving the basal region of
the right temporal lobe.

Fig 8. Patient 8. CT scan showing bilateral orbitofrontal contusions.

in the lateral basotemporal area for all 3 patients. In 1
patient (Patient 1) metabolic activity in this region was
slightly below 2 SD of the mean whole-brain metabolic
activity, and the A1 was more than 2 SD below the
mean A1 for the normal control group (Fig 9) (Table).
Another patient (Patient 2) showed significant metabolic asymmetries (right side < left side) for the lateral
basotemporal (Fig lo), superior frontal, and parietal
regions of the cortex. The metabolic activity for each
of these regions was greater than 1 SD below the mean
whole-brain metabolic activity, and the respective AIs
were more than 2 SD below the respective A1 means
for the normal control group (see Table). One patient
(Patient 3) showed a significant metabolic asymmetry
(right side < left side) only for the lateral basotemporal
region (Fig 11). Metabolic activity in this region was
more than 1 SD below the mean whole-brain metabolic activity, and the A1 was more than 2 SD below
the mean A1 for the normal control group (see Table).

Fig 7. Patient 7. Noncontrasted C T scan showing a hemorrhagic lesion in the right temporal lobe.

656 Annals of Neurology Vol 27 No 6 June 1990

Discussion
We performed imaging and metabolic studies in a new
series of patients with secondary mania, and there were
several important findings. First, all 8 patients showed
damage in the right hemisphere. Second, 4 of the 5
patients with cortical lesions had involvement of the

Fig 9. Patient 1 "Fluorodeoxyglucose PET scan showing hypometabolism in the right lateral basotemporal area of the cortex
(arrows). Line indicates thefull extent of the temporal area of
the cortex. The plane of the PET scan is ventral to the plane
showing the lesion on MRI. LTC = lateral temporal region;
MTC = medial temporal region; OFC = orbitofrontal region;
BST = brainstem.
~

Fig 10. Patient 2. "Fluorodeoxyglucose PET scan showing hypometabolism in the right lateral basotemporalregion ofthe cortex (arrows).Abbreviations are as in Figure 9 legend. The plane
of the PET scan is ventral to the plane showing the lesion on
MRI.

Regional Cerebral Glucose Metabolic Rates (mg of Glucose1100 gmlmin) and Asymmetry Indexes (AI)"
~~~

~

~

Lateral temporal
Left
Right
A1
Rightlleft
Inferior frontal
Left
Right
A1
Righdleft
Superior frontal
Left
Right
A1
Righdleft
Parietal
Left
Right
A1
Righdleft
Mean whole-brain
metabolic rate

Patient 1

Patient 2

Patient 3

Normal Control Values

7.4 (.6)
6.5 (.5)
- 13.5
0.88

7.2 (.9)
5.4 (.6)
-27.6
0.75

5.9 (.5)
5.3 (.7)
- 10.4
0.90

8.2 (2.6)
8.1 (2.5)
-2.2 (.7)
0.99

8.3 (.7)
7.7 (1.0)
- 8.2
0.93

6.5 (1.5)
6.1 (.9)
- 6.6
0.94

5.6 (1.3)
5.5 (1.3)
-2.5
0.98

10.4 (4.0)
10.3 (4.0)
- 1.0 (.9)

8.7 (.9)
8.4 (.4)
- 2.5
0.97

8.6 (3)
7.3 (.8)
- 17.9
0.85

6.8 (.7)
6.9 (.6)
1.5
1.01

10.4 (3.9)
10.7 (4.4)
1.9 (1.3)
1.03

7.6 (.6)
7.3 (.6)
- 3.3
0.96
7.7 (1.3)

8.0 (.4)
7.4 (.6)
- 8.7
0.93
7.5 (1.1)

6.4 (.6)
6.5 (.4)
1.9
1.oo
6.1 (.6)

9.6 (3.5)
9.6 (3.4)
-.2 (3.7)
1.00
9.9 (3.6)

0.99

"SDs are in parentheses.

Starkstein et al: Secondary Mania

657

Fig 11. Patient 3. ‘8FluorodeoxyglucosePET scan showing hypometabolism in the right lateral basotemporal region of the cortex (arrows). Abbreviations are as in Figure 9 legend. The plane
of the PET scan is ventral to the plane showing the lesion on

CT.

basotemporal region of the cortex. Third, all 3 patients
with subcortical damage showed metabolic deficits in
the right basotemporal region, remote from the brain
lesion.
Several limitations of this study should be mentioned. Since we did not perform brain metabolic studies in patients with similar lesions to the 3 manic patients but without mania, we cannot be sure about the
specificity of this finding. Brain metabolic studies were
carried out while patients were in the manic state and
they were not repeated when they were euthymic. Future studies may determine if the present metabolic
findings represent a “state” or “trait.” Another limitation is that 2 of the 3 patients were takmg lithium (but
no other drug) at the time of the brain metabolic studies. Both patients, however, showed brain metabolic
asymmetries similar to those in the drug-free patient.
An important issue is whether the present psychiatric findings are more related to the jocularity and disinhibition frequently associated with right hemisphere
damage than to a secondary mania. In order to avoid
this nosological problem, we examined all our patients
with a standardized psychiatric instrument (the PSE),
and a diagnosis of organic affective disorder, manic
type was made using DSM-111-R criteria. Thus, these
patients had more than just jocularity and disinhibition. They manifested the whole syndrome of mania
including increased libido, elevated self-attitude, de658

Annals of Neurology

Vol 27

No 6 June 1990

creased amount of sleep, delusionary beliefs, and feelings of euphoria. Because of the overlap of symptoms,
however, we cannot be sure whether these manic patients may also have had a separate syndrome of jocularity and disinhibition (assuming the mechanisms of
mania and jocularity are different). This interesting issue will require further research.
In a previous study of lesion location in a different
series of patients with secondary mania, we found lesions clustering in limbic and limbic-related areas with
strong connections to the frontal lobes 121. Since the
orbitofrontal region of the cortex is one of the main
limbic efferent channels to the hypothalamic-hypophysial complex and the visceral motor system, we hypothesized that dysfunction of the orbitofrontal region
may underlie the production of the somatic and mood
symptoms of secondary mania. Findings in the present
study suggest that dysfunction of the basotemporal
area of the cortex may also play a role in the production of secondary mania. Although the mechanism by
which a basotemporal lesion may produce manic symptoms remains speculative, the basotemporal area is an
important region of the limbic system. Mesulam and
Moran and coworkers described four major inputs to
the temporopolar area of the cortex in primates [14,
151: (1) frontal and temporal heteromodal association
area; (2) modality specific auditory and visual association areas; ( 3 ) paralimbic areas of the orbitofrontal,
paraolfactory, insular, and parahippocampal regions;
and (4) limbic structures such as the amygdala, hippocampus, and olfactory allocortex. These same authors suggested that behavioral changes produced by
temporopolar lesions may result from breakdown of
sensory limbic integration 114, 151. Temporopolar
dysfunction may also result from posterior orbitofrontal lesions. Both structures share prominent anatomical
connections 1151 which may underlie the association
between frontal-related volitional and psychomotor
behaviors and limbic-related emotional drive 1161.
The second implication of this study is that lesions
outside the basotemporal region may produce secondary mania through a remote metabolic effect (diaschisis). While it may be argued that the remote hypometabolism in the right basotemporal region is
nonspecific (i.e., unrelated to the development of secondary mania), other investigators found that subcortical lesions similar to the ones found in our patients
with secondary mania have not been associated with
diaschisis in the basotemporal area 1171.
The third implication of this study is that dysfunction of the right hemisphere, as compared with the left
hemisphere, may be more important in the development of mania. Both the brain lesions and the remote
hypometabolic effects were localized to the right hemisphere. In a rat model of focal brain injury, we found
that right but not left frontolateral cortical lesions pro-

duced hyperactivity as well as depletions of norepinephrine in widespread brain regions and an increased
turnover of dopamine in the nucleus accumbens 118,
191. We also recently reported that stroke in the right
but not the left hemisphere in humans leads to an
increase in cortical S2-serotonin receptor binding in
temporal and parietal regions of the cortex [8]. Thus,
in both rats and humans there is an asymmetrical biochemical response to brain injury, depending on
whether the right or left hemisphere is injured. It is
possible that mania may result from asymmetrical
changes in biogenic amine neurotransmitter function
following stroke in the right hemisphere. This biogenic
amine dysfunction may also be most pronounced in
the lateral basotemporal area, thus leading to the development of mania through tonic influences on the
entire limbic pathway.
This work was supported in part by the following National Institutes of Health grants: Research Scientist Award MH-00163 (to
R. G. R.), NS-15178, NS-15080, and MH-40355. This work was
also supported in part by a grant from the University of Buenos
Aires (to S. E. S.), a Young Investigator Award from the National
Alliance for Research in Schizophrenia and Depression (to S. E. S.),
and a grant from the Instituto Di Tella (to M. L. B.).
We wish to thank Henry Holcomb, MD, Bernard Sadzot, MD,
Jeffrey Leal, and David Clough for their assistance with PET data
acquisition and analysis; and Allan A. Wilson, PhD, and Hayden T.
Raven, PhD, for the preparation of FDG.

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659