Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol47.Issue11.2000:
Muscle Biopsy, Macro EMG, and Clinical
Characteristics in Patients with Schizophrenia
Lena Flyckt, Jörgen Borg, Kristian Borg, Tor Ansved, Gunnar Edman,
Lars Bjerkenstedt, and Frits-Axel Wiesel
Background: In a previous study of motor unit properties
in patients with schizophrenia, muscle fiber histologic and
electrophysiologic abnormalities were observed. The
present study was designed to compare patients with
schizophrenia with healthy control subjects with regard to
muscle fiber histology and motor unit function. A second
objective was to relate these variables to clinical
characteristics.
Methods: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSMIII-R) and 27 matched control subjects were included in
the study. Muscle biopsies were performed either in m.
tibialis anterior or m. vastus lateralis. Electromyographic
recordings (macro EMG) were made from the m. tibialis
anterior motor units. Psychiatric ratings included the
PANSS and extrapyramidal side effects.
Results: Seven of the muscle biopsy specimens from the
patients and one from the control subjects were classified
as abnormal (p 5 .049). The most frequent abnormality
was atrophic muscle fibers. Eight patients and no control
subjects exhibited pathological macro EMG (p 5 .032).
The findings were present in chronic as well as in
first-episode patients with schizophrenia.
Conclusions: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle
biopsy or the macro EMG investigations. The results
indicate that either a common pathologic process or
different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane
function. Biol Psychiatry 2000;47:991–999 © 2000 Society of Biological Psychiatry
Key Words: Muscle biopsy, macro EMG, schizophrenia,
muscle fiber atrophy, fiber density, motor unit
From the Department of Psychiatry, Karolinska Institutet, Danderyds Hospital (LF,
GE, LB) and the Department of Clinical Neuroscience, Neurology, Karolinska
Hospital (JB, KB, TA), Stockholm, and the Department of Neuroscience,
Psychiatry, Uppsala University Hospital, Uppsala (F-AW), Sweden.
Address reprint requests to Lena Flyckt, M.D., FoUU, Department of Psychiatry,
Danderyds Hospital, S-182 88 Danderyd, Sweden.
Received May 28, 1999; revised November 2, 1999; accepted November 10, 1999.
© 2000 Society of Biological Psychiatry
Introduction
T
he evidence of neuromuscular abnormalities in
schizophrenia is extensive. The type of abnormalities
range from skeletal muscle fiber changes (Meltzer and
Crayton 1975; Ross-Stanton et al 1980), alterations of
a-motoneuron excitability (Crayton et al 1977a), increased
motor unit fiber densities (Crayton et al 1977b; Crayton
and Meltzer 1979), and increased branching of terminal
motor nerves (Meltzer and Crayton 1974b; Ross-Stanton
and Meltzer 1981) to elevated levels of muscular enzymes
(Meltzer and Crayton 1974a; Zweig et al 1981). The
nature of the neuromuscular changes in patients with
schizophrenia is far from clear, but most studies have
concluded that they are secondary to neurogenic processes
of either central or peripheral origin (Borg et al 1987;
Crayton et al 1977a, 1977b; Crayton and Meltzer 1979;
Meltzer and Crayton 1974b, 1975; Ross-Stanton and
Meltzer 1981; Ross-Stanton et al 1980).
In the studies by Meltzer and coworkers, muscle fiber
abnormalities including atrophic fibers, “type-grouping,”
“central core fibers,” and “ring fibers” were found in about
half of the psychotic patients (Meltzer 1972; Meltzer and
Crayton 1975). In healthy controls subjects, muscle fiber
abnormalities were found in two of 34 cases (6%) (Meltzer
et al 1976). Similar abnormalities have been found in
patients with psychotic mood disorders, indicating that
they are not specific to schizophrenia (Meltzer 1973).
Thus, these findings may be associated with the occurrence of psychotic symptoms rather than a categorical
diagnosis. In a study of schizophrenic patients by Borg and
coworkers (1987), the muscle biopsy findings included
atrophic fibers, central nuclei, “moth-eaten fibers,” “ring
fibers” fiber splitting, and subsarcolemmal glucogen droplets. Neuroleptic medication could not explain the observed findings because they were also present in neuroleptic-free patients. The histologic changes observed have
been described in neurogenic as well as myogenic disorders. Because of the nonspecific nature of the muscular
changes, other concurrent findings must be considered to
better understand its causal connections. Thus, electrophysiologic investigations of single motor unit properties
0006-3223/00/$20.00
PII S0006-3223(99)00295-4
992
L. Flyckt et al
BIOL PSYCHIATRY
2000;47:991–999
demonstrated impaired distal impulse propagation,
whereas the axonal conduction velocity and refractory
period were normal, indicating a peripheral nerve involvement in the patients with schizophrenia (Borg et al 1987).
The findings of neuromuscular changes in patients with
schizophrenia are intriguing and deserve further exploration to find possible pathophysiologic mechanisms. The
aim of this study was to evaluate the hypothesis that
muscle fiber abnormalities are secondary to loss of distal
neural influence in patients with schizophrenia. The novel
approach to this question was the inclusion of patients
with first-episode schizophrenia, as well as the use of the
macro electromyographic (EMG) method because of its
ability to discern collateral sprouting, a sign of neuropathy, and thereby disentangling primary or myogenic
muscle fiber abnormalities from those secondary to distal
neuropathy. Another aim was to investigate the relationship between motor unit properties and clinical
characteristics.
Table 1. Sociodemographic and Clinical Characteristics of
Schizophrenic Patients and Healthy Control Subjects
Variable
Patients
(n 5 27)
Control
subjects
(n 5 27)
15 (56%)
12 (46%)
15 (56%)
12 (44%)
32.7
6.31
21– 45
32.2
7.23
21– 47
20.5
12.0
2–96
0.0
0.0
0–0
58.2
30.0
4 –192
0.0
0.0
0–0
259.4
200.0
100 – 800
0.0
0.0
0–0
Clinical Measures
Gender
Male
Female
Age (years)
Mean
SD
Range
Duration of schizophrenic
symptoms (months)
M
Md
Range
Duration of medication (months)
M
Md
Range
Neuroleptic medication (daily
dosage in equivalents of
chlorpromazine)
M
MD
Range
PANSS
Positive symptoms
M
SD
Range
Negative symptoms
M
SD
Range
Total symptoms
M
SD
Range
ESRS (observed symptoms)
Parkinsonism
M
SD
Range
Akathisia
M
SD
Range
Tardive dyskinesia
M
SD
Range
Dystonia
M
SD
Range
GAF score
M
SD
Range
The symptoms of illness were rated according to the Positive and
Negative Syndrome Scale (PANSS; Kay et al 1987). The Global
PANSS, Positive and Negative Syndrome Scale; ESRS, Extrapyramidal Symptom Rating Scale; GAF, Global Assessment of Functioning scale.
Methods and Materials
Subjects
Patients with schizophrenia were consecutively recruited on
admission to a psychiatric clinic in Stockholm. To be included,
the patients had to meet the DSM III-R (American Psychiatric
Association 1987) criteria for schizophrenia and be between 18
to 45 years of age. A clinical diagnostic interview and the
Structured Clinical Interview for the DSM-III-R (SCID; Spitzer
et al 1987) were performed independently by two clinicians (GE
and LF). Twenty-seven patients gave their informed consent to
enter the study. Twelve of these were experiencing their firstepisode of schizophrenia, and 15 were patients with chronic
schizophrenia. The two clinicians (GE and LF) agreed in their
diagnosis in 26 of 27 cases (96%). In the case of disagreement,
consensus was reached after consultation. If a first-episode
patient had less than a 6-month history of illness, he or she was
followed up to confirm the diagnosis of schizophrenia. For each
of the included patients, one healthy control subject with matching age and gender was selected from a group of 55 normal
individuals (Table 1). The exclusion criteria for patients and
control subjects were a history of drug abuse, head injury, or any
neurological or serious somatic disease. All subjects were asked
about their physical activity and dietary habits, and those
considered aberrant were not included (e.g., top-level athletes,
binge or anorectic eating habits, vegetarians, allergy to certain
foods). Control subjects were excluded if they filled the criteria
for a psychiatric diagnosis (DSM-III-R) or had a family history
in first- or second-degree relatives of psychiatric illnesses. There
was no overlap between the subjects in the present study and the
study by Borg et al (1987).
14.9
5.23
7–26
7.8
1.16
7–11
19.4
6.63
9 –33
8.5
1.50
7–12
68.5
14.44
48 –96
34.6
3.59
30 – 44
12.9
7.02
3–36
1.9
3.13
0 –12
0.8
1.01
0–4
0.0
0.00
0–0
1.8
3.36
0 –11
0.2
0.58
0 –2
1.7
3.52
0 –13
0.0
0.00
0–0
50
12.0
20 –70
84
4.0
75– 89
Neuromuscular Abnormalities in Schizophrenia
Assessment of Functioning scale (GAF; American Psychiatric
Association 1987) was used to rate the level of functioning. The
Extrapyramidal Symptom Rating Scale (ESRS; Chouinard et al
1980) was used to rate side effects of neuroleptic medication. All
clinical ratings were made when the subject entered the study.
Because it was not always possible to perform the muscle biopsy
in the acute phase, the clinical ratings occasionally preceded the
biopsy by some weeks. Responsiveness to neuroleptic medication was based on a global rating of recovery (“yes, no, partly”)
made by a trained clinician (LF) about 6 months after the
initiation or adjustment of neuroleptic medication.
Neuroleptic Medication
Two of the first-episode schizophrenic patients had never taken
medication for their illness, and one of the chronic patients had
been off neuroleptic medication for 6 months. Twenty patients
were on conventional neuroleptics, and four were on clozapine.
The mean dosage (equivalents of chlorpromazine; Beckman and
Laux 1990) and mean duration of neuroleptic medication at the
time for the muscle biopsy are shown in Table 1. Additional
medication for day and night sedation (benzodiazepines) was
allowed and a few patients were on low doses of oxazepam and
nitrazepam.
Muscle Biopsy Procedure
Muscle biopsy was performed in patients (n 5 26) and control
subjects (n 5 26) either in m. tibialis anterior (TA) or in m.
vastus lateralis (VL) using the percutaneous conchotome method
(Radner 1962). The reason for the choice of two muscles instead
of one was to increase the sites of investigation and thereby
increase the representativity. The muscle biopsies from the
patients were performed in the same muscle as the matching
control subject. The biopsy material was immediately frozen in
Freon 22, which was kept at its melting point (2190°C) by liquid
nitrogen, and then placed in a freezer at 275°C until further
processed. Sections of 10 –15 mm were cut in a cryostat operating
at 225°C. One patient dropped out of the study because of
noncompliance.
Histochemical and Morphometrical Techniques
Cross-sections were stained with haematoxylin-eosin and modified tricrome (Engel and Cunningham 1963) for myofibrillar
ATPase (mATPase; Padykula and Herman 1955) and NADH-TR
(Scarpelli et al 1958). The classification of muscle fiber types
was based on their mATPase staining characteristics, as described by Brooke and Kaiser (1970).
The cross-sectional areas of the muscle fibers were measured
directly from the microscope via a CCD camera (Hamamatsu
C3077, Hamamatsu Photonica KK, Japan) connected to an
image-analysis processor (Vidas, Kontron Bildanalyse, GmbH,
Munich). Measurements were made on 100 type I and type II
fibers from each biopsy specimen. The muscle fibers were
selected from a central part of the biopsy specimen considered
not to contain artifacts. If the total number of fibers of respective
type was smaller than these numbers, then all fibers of that type
were measured.
BIOL PSYCHIATRY
2000;47:991–999
993
Classification of Histopathologic Changes in
Muscle Biopsies
The muscle biopsies were blindly classified as normal and
abnormal by two neurologists (KB and TA). The biopsy was
classified as abnormal if the specimen contained any of the
following changes: central nuclei in more than 3% of the fibers,
more than eight atrophic muscle fibers, splitting phenomena,
inclusion bodies, more than three irregular staining of formazan
granules, and the presence of type grouping. The criteria of the
classification are based on the work of Mastaglia and Detchaut
(1992). A neurologist (TA), blinded to the diagnosis, estimated
modal distributions of fiber areas by inspection of fiber area
histograms made for each subject.
Macro EMG
The first 22 patients and 10 control subjects included in the study
were investigated with macro EMG. Electromyographic recordings were made from the m. tibialis anterior motor units by
macro EMG needle electrodes (Medelec 17915) and displayed
on a Medelec oscilloscope (MS92B no 67127) connected to a
microcomputer (Victor PCII). The needle electrode is a modified
single fiber EMG electrode. One single fiber recording was
registered from a side port on the needle electrode with an uptake
area of one or two muscle fibers. The single fiber action potential
was used to trigger the recordings of simultaneous electrical
activities picked up by the electrode shafts from “all” muscle
fibers belonging to the same motor unit. By averaging during
slight voluntary activation, the electric activity was obtained as
the macro EMG action potential.
Recordings were made from motor units recruited at slight
voluntary activation, a prerequisite for the analysis. Because one
of the patients was unable to keep a slight and stable activation,
the subject was excluded. Macro EMG recordings were analyzed
according to Stålberg (1990) using Stålberg Intersoft program
Macro 4.1 1992. Data collected from the patients were compared
with published age-related reference data from a previous study.
(Stålberg and Fawcets 1982) and 10 age-and gender-matched
control subjects from the present study. Two or more motor unit
potentials with an amplitude, area, or median value outside the
defined range (6 2 SDs) was considered pathological (Stålberg
1990; Stålberg and Fawcets 1982). The fiber density was defined
as the mean number of single muscle fiber action potentials at
each of the 20 macro EMG recording sites according to established criteria (Stålberg and Trontelj 1979).
Statistics
Clinical data were summarized using conventional descriptive
statistics: means, standard deviations, median ranges, and frequencies. Dichotomous variables were analyzed with the chisquare method or Fisher’s exact test, two-tailed. Parametric
Student’s t test was applied for group-wise comparisons of
continuous variables. In case of skewed distributions with
outliers, nonparametric Mann–Whitney U test was applied in the
group comparisons (e.g., means of cross-sectional fiber areas and
daily doses of equivalents of chlorpromazine) and Kendall’s rank
994
BIOL PSYCHIATRY
2000;47:991–999
Figure 1. Cryostat cross-section of muscle biopsy, stained with
haematoxylin-eosin, from a schizophrenic patient. Three angulated atrophic muscle fibers are present in the center. Original
magnification 3250.
correlation for relationships between variables. A value of p ,
.05 was considered to be statistically significant. Because of the
low power of the comparisons, no correction of multiple comparisons was made so as not to increase the risk of committing
type II errors. By making planned comparisons, the increased
risk of type I errors was taken into account.
Results
L. Flyckt et al
pathological macro EMG recordings (Fisher’s exact test 5
0.032; Table 3). Figure 2 illustrates the recordings from
two motor units, one with a larger amplitude and area
(Figure 2A) and the other with an amplitude and area
within the normal range (Figure 2B). The upper traces
show the averaged single fiber action potentials, and the
lower traces show the averaged macro EMG potentials.
Figure 3 depicts the amplitudes and areas from all 20
motor units recordings in two patients (A and B). Figure
3A shows the data from a patient with a shift of the motor
unit potentials toward the upper limit for amplitude and
area. Six motor unit potentials were outside the normal
range (indicated by the outer square border), and the
median value also was outside the normal range (indicated
by the inner square border). Figure 3B shows the corresponding data from a patient with ordinary motor unit
potential amplitudes and areas.
Fiber density (FD; i.e., the mean of the number of single
muscle fiber potentials at each recording site) was calculated for all patients and control subjects. In the eight
patients with pathological macro EMG motor unit potentials, fiber densities ranged from 1.1 to 2.0 (mean 5 1.4),
in the 13 patients with normal macro EMG from 1.1 to
1.9.(M 5 1.3), and in the control subjects from 1.1 to 1.7
(M 5 1.4). There were no significant differences in fiber
density among these groups.
Muscle Biopsy Findings
Histologic changes were found in seven patients and in
one control subject (Fisher’s exact test 5 0.049). The most
frequent abnormality in the patients was atrophic muscle
fibers scattered or in groups (Figure 1 and Table 2). On
ATPase staining, the atrophic fibers were of both type I
(slow twitch) and type II (fast twitch). Regarding other
abnormalities in modified trichrome and NADH-TR
stained sections such as vacuols, ring fibers, tubular
aggregates, subsarcolemmal glucogen droplets, and irregular staining of formazan granules, there were no significant differences between the biopsies from patients and
those of control subjects.
Mean muscle fiber areas of type I, type II a, or type II
b did not differ significantly between patients and control
subjects. No differences between patients and control
subjects in modal distributions of fiber area histograms
was observed. There was no significant difference in mean
fiber area between the patients classified as normal or
pathological in muscle fiber morphology.
Macro EMG
Macro EMG recordings were available from 20 motor
units in each of the 21 patients. According to the used
criteria (see Methods and Materials), eight of the schizophrenic patients and none of the control subjects exhibited
Relationships among Muscle Biopsy, Macro EMG,
and Clinical Characteristics
Seven of twenty-six patients exhibited muscle biopsy
abnormalities and 8 of 21 patients a pathological macro
EMG. Only three patients showed abnormalities in both
investigations [x2(1) 5 0.36, p 5 .550].
No relationship was found between symptoms of illness
and muscle biopsy abnormalities except in patients with
positive symptoms, especially delusions (Z 5 1.6657, p 5
.09). There were no significant differences between patients with and without muscle fiber abnormalities in the
daily dosage of neuroleptic medication, lifetime exposure
(months) to neuroleptic medication, GAF, or any of the
ESRS items. Patients who were experiencing their first
episode of schizophrenia (n 5 12) or who had a chronic
course (n 5 14) did not differ in muscle fiber morphology.
Three chronic and four first-episode schizophrenic patients had muscle fiber abnormalities. There was no
relationship between increased age or responsiveness to
medication and muscle biopsy findings (Table 2).
Patients with pathological and normal macro EMG did
not differ significantly in daily dosage (equivalents of
chlorpromazine), lifetime exposure (months) to neuroleptic medication, or responsiveness to neuroleptic medica-
Neuromuscular Abnormalities in Schizophrenia
995
BIOL PSYCHIATRY
2000;47:991–999
Table 2. List of Patient Characteristics
First
episode
Macro
EMG
Muscle
biopsy
Male
Male
Male
No
No
No
Pathologic
Pathologic
Pathologic
Normalb
Normalc
Pathologicb
Male
Male
Male
Male
Male
Male
Male
Male
Male
No
No
No
No
No
No
No
Yes
Yes
Pathologic
Normal
Normal
Normal
Normal
Pathologic
Normal
Pathologic
Normal
Normalc
Normalb
Normalc
Normalc
Normalc
Normalc
Normalc
Normalc
Pathologicc
Male
Male
Male
Female
Female
Female
Female
Female
Yes
Yes
Yes
No
No
No
No
No
Normal
Not done
Not done
Normal
Pathologic
Normal
Not done
Normal
Not done
Normalc
Pathologicc
Normalc
Pathologicb
Normalc
Normalc
Pathologicc
Female
Female
Yes
Yes
Normal
Normal
Normalc
Pathologicc
Female
Female
Female
Female
Female
Yes
Yes
Yes
Yes
Yes
Normal
Not done
Not done
Pathologic
Not done
Pathologicc
Normalc
Normalc
Normalc
Normalc
Gender
Type of muscle
fiber abnormality
Moth-eaten fibers,
I—atrophy
Scattered atrophic
fibers
I—atrophy
II–atrophy
II b—atrophy,
central nuclei
Scattered atrophic
fibers
II b—atrophy
GAF
Lifetime
exposure to
neurolepics
(months)
Equivalents of
clorpromazine
Response to
neuroleptic
medication
65
40
45
18
144
192
100
0d
175
Yes
Partly
No
49 (60)
173 (24)
120 (96)
67 (12)
23 (8)
47 (18)
132 (48)
7 (12)
16 (9)
50
37
40
45
45
50
65
53
20
48
36
120
63
12
27
120
7
16
325e
150
800e
350
200
200
375e
200
100
Partly
Partly
No
No
Yes
Partly
No
Yes
Yes
15 (12)
17 (12)
10 (9)
108 (24)
305 (2)
94 (12)
108 (12)
180 (6)
50
65
70
60
50
45
67
50
4
0
10
88
180
74
69
120
200
0f
150
200
350e
325
200
225e
Yes
No
No
Yes
No
Yes
Yes
Partly
19 (12)
56 (12)
70
50
16
12
150
250
Yes
Yes
8 (10)
127 (6)
12 (6)
7 (7)
2 (48)
35
35
40
65
45
8
20
12
4
0
200
500e
200
300
0f
Yes
Partly
Partly
Yes
n/a
Duration of
illness in
monthsa
31 (24)
168 (4)
192 (48)
EMG, electromyogram; GAF, Global Assessment of Functioning scale.
The figures indicate the time from the first psychiatric contact to the investigation. Figures within parentheses show the time from the onset of symptoms to the first
psychiatric contact.
b
The muscle biopsy was performed in the m. vastus lateralis.
c
The muscle biopsy was performed in the m. tibialis anterior.
d
The patient had been off medication for 6 months.
e
Atypical neuroleptic medication (clozapin).
f
The patients were neuroleptic naive.
a
tion. There were no significant differences between these
patient groups in age; in the PANSS, ESRS, or GAF
scores; or in whether the patients were first episode (n 5
7) or had a chronic course (n 5 14). Two first episode and
six chronic patients had pathological macro EMG.
Discussion
Neuromuscular abnormalities were found in 13 patients
(48%), either in the muscle biopsy or macro EMG investigations, in both chronic and first-episode schizophrenic
patients. The muscle biopsy findings in seven of the
patients included angulated atrophic muscle fibers, scattered or in groups. Atrophy is the most common response
of a muscle fiber to loss of neural influence. Angulated
small fibers, previously normal in size, are considered to
be the result of a neural degeneration and subsequent
atrophy. Scattered or randomly distributed fiber atrophy
may be present in the early phase of neural loss. These
findings are in accordance with the results from earlier
studies (Crayton et al 1977a, 1977b; Crayton and Meltzer
1979; Meltzer and Crayton 1975; Ross-Stanton et al 1980;
Ross-Stanton and Meltzer 1981).
In these earlier studies, distal muscle groups were
investigated (m peroneus brevis for the muscle biopsy and
m flexor digitorum longus for EMG studies), but in our
study, more proximal muscles were studied (m tibialis
anterior and m vastus lateralis for the muscle biopsy and m
tibialis anterior for the macro EMG). The findings seem to
be present regardless of the site of investigation, indicating
996
L. Flyckt et al
BIOL PSYCHIATRY
2000;47:991–999
Table 3. Macro Electromyographic Data in Schizophrenic Patients and Matched Control Subjects
Amplitude
(mV)
Subject
Area
(mV 3 ms)
Fiber density
(n)
Classification
Gender
P
C
P
C
P
C
P
C
Malea
Female
Male
Male
Male
Male
Male
Femalea
Femalea
Malea
Female
Male
Malea
Male
Male
Femalea
Female
Femalea
Male
Female
254
278
239
298
479
478
532
307
254
239
181
176
181
187
195
181
185
210
141
170
186
190
190
1709
1287
1554
1345
1988
1936
2331
2079
1279
1020
906
684
960
955
1191
1154
1130
1258
663
748
1207
1164
837
1.3
1.1
1.2
1.2
1.1
2.2
1.5
1.8
1.3
1.3
1.3
1.1
1.3
1.4
1.4
1.4
1.4
1.9
1.5
1.4
1.6
1.1
1.6
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
268
257
199
186
215
156
184
1450
968
972
1018
1001
810
1041
1.7
1.2
1.3
1.4
1.6
1.5
1.4
Normal
Normal
Normal
Normal
Normal
Normal
Normal
P, patient; C, control subject.
a
Indicates a first-episode schizophrenic patient.
that the peripheral motor neurons and skeletal muscles are
affected throughout the body.
Pronounced physical inactivity may result in muscle
fiber atrophies (Edström and Grimby 1986; Houston et al
1979; Lindboe and Platou 1982). If the muscle fiber
atrophies among the patients in our study were caused by
inactivity, primarily the type 2 b fibers would have been
affected (Houston et al 1979), but atrophies were found in
all types of fibers. Thus, inactivity did not seem to be the
reason for the findings. In a study by Borg et al (1987) the
muscle biopsy findings included atrophic fibers, central
nuclei, and “moth-eaten fibers,” indicating loss of lower
motor neurons in accordance with our study. We did not
replicate the findings of vacuols, ring fibers, tubular
aggregates, subsarcolemmal glucogen droplets, and irregular staining of formazan granules, however. In our study,
about half of the patients were women and half were
experiencing their first episode of schizophrenia; in the
study by Borg et al (1987), there were no women and only
one patient was first episode. Studies have indicated
gender-related differences in muscle fiber morphology,
although this aspect was not observed in our study
(Glenmark et al 1992). Thus, the large proportion of
first-episode schizophrenic patients in our study seems to
be the most likely reason for the different findings.
The macro EMG recordings were pathological in 8 of
21 patients. The motor unit potentials had increased
amplitude and area compared with data from age- and
gender-matched control subjects, whereas fiber densities
did not differ. The interpretation of the abnormal macro
EMG data must consider factors affecting the muscle
fibers, as well as the peripheral and central neurons
(Stålberg 1990).
Muscle fiber hypertrophy may cause an increase of the
motor unit potential (Stålberg 1990); however, no hypertrophic fibers were found in the biopsies of the schizophrenic patients. Other factors have to be considered,
including those influencing the muscle fiber action potential (E. Stålberg, personal communication). Thus, disturbed muscle fiber membrane function may be consistent
with an increase of the macro EMG potential and retained
fiber density.
Increased fiber density, a sign of denervation and
reinnervation by collateral sprouting, has been described
previously in studies of psychotic patients (Crayton et al
1977b; Meltzer and Crayton 1974a; Ross-Stanton and
Meltzer 1981). The patients in these studies exhibited
different psychotic conditions, however; our study included a large number of first-episode schizophrenic
patients, a variable not previously investigated in relation
to fiber density. Therefore, it is possible that the differences in fiber density between the studies may indicate a
progress in motor unit pathology with the duration of
illness. We did not find any relationship between the
disease duration and motor unit abnormalities, however.
Moreover, muscle fiber abnormalities were found in four
Neuromuscular Abnormalities in Schizophrenia
BIOL PSYCHIATRY
2000;47:991–999
997
Figure 2. Examples of electromyogram (EMG) recordings
showing the average single muscle fiber potential (upper tracings) and macro EMG potential (lower tracings) of two motor
units (A and B). The macro EMG potential amplitude and area
were (A) above the normal range for one motor unit and (B)
within the normal range for the other.
first-episode schizophrenic patients, and pathological
macro EMG were found in two first-episode schizophrenic
patients, demonstrating that the changes in motor unit
properties begin in the early course of schizophrenia and
are not the result of a chronic course. Differences between
the results of the two studies may be attributablex to
contrasting methods (single fiber EMG vs. macro EMG),
different patient samples (other psychotic conditions vs.
schizophrenia), or both.
Loss of lower motor neurons with a compensatory,
collateral reinnervation might cause an enlargement of the
macro EMG motor unit potentials; however, there was no
relationship between the macro EMG and the muscle
biopsy findings. Further, the fiber density did not differ
between patients with and without increased action potentials. This argues against a loss of lower motor neurons. A
selective loss of low-threshold, type I motor units may be
consistent with increased macro EMG potentials and
normal fiber density, but the muscle biopsy data did not
support that interpretation. Thus, the present electromyographical data do not permit any conclusion about a loss of
lower motor neurons.
The possibility of a disturbed central activation must
also be considered. In normal subjects, low threshold
motor units have smaller motor unit action potentials than
do high-threshold motor units (Milner-Brown et al 1973;
Stålberg 1990). If there is a changed central activation
pattern with an earlier recruitment of larger motor units in
schizophrenic patients than in normal subjects, it might
explain the observed macro EMG changes. This might
then be attributable to a primary disease process affecting
both the central and peripheral nervous system.
The fact that the histologic abnormalities were found in
some but not all patients, as well as the low concordance
between the muscle biopsy and macro EMG findings may
be caused by a high rate of false negative muscle biopsy
specimens. In our study, the site of investigation included
Figure 3. Macro electromyogram recordings from two patients
with (A) pathological and (B) normal motor unit potential
amplitude and area values. The boxes show the 20 single motor
unit values, and the crosses show the median of these. The outer
square border indicates the normal range of motor unit potentials,
and the inner square border indicates the normal range of the
median value from an age-matched healthy reference population
(Stålberg and Fawcets 1982).
two different muscle groups; however, it is not possible to
eliminate the false-negative problem because there are
ethical issues associated with multiple biopsies in the same
patient. If the lack of concordance is genuine, however, the
interpretation may be that the neuromuscular systems—
both central and peripheral—are affected at different
levels by one common or several underlying factors, but
the processes have reached different stages.
Neuromuscular abnormalities may be connected to
disease-related factors, such as clinical characteristics and
neuroleptic medication; however, no relationship to symptoms, duration of illness, or function were found. Furthermore, the duration, side effects, and dosage of neuroleptic
medication were not related to the neuromuscular results.
In a previous study, of the m. tibialis anterior, drug-free
patients exhibited the same neuromuscular pathology as
those on neuroleptic drugs (Borg et al 1987). This indicates the neuromuscular changes are not related to the
symptoms, a chronic course or neuroleptic medication.
In conclusion, our data add to the accumulating number
of observations regarding motor-system disturbances on
multiple levels in schizophrenia, corresponding to previous suggestions by Meltzer and Crayton (1974a, 1975). It
also provides new insights, however. The neuromuscular
findings seem to be present in first-episode schizophrenic
patients, possibly in skeletal muscle groups throughout the
body. The combination of findings, that is, an increased
998
BIOL PSYCHIATRY
2000;47:991–999
amplitude and area of the muscle fiber action potential
together with a retained fiber density, point to changes in
the electrophysiological properties of the cell membrane.
Furthermore, the lack of concordance between findings
indicates that the pathophysiologic processes may operate
independently at different levels. Looking for a possible
factor in common, one may speculate about relation to the
observations of increased phospholipase A2 activity in
blood cells (Ross et al 1997), regarded as evidence of an
increased breakdown of cell membranes. This also seems
to take place in the brain, as indicated by reduced levels of
phosphomonesters and increased levels of phosphodiesters
in schizophrenic patients, determined by magnetic resonance spectroscopy (Pettegrew et al 1991). An altered cell
membrane composition and function in schizophrenia, as
previously suggested (Horrobin 1998; Wiesel and
Bjerkenstedt 1996), may be consistent with the neuromuscular findings in the present study.
This study was supported financially by the North-East Health Care
district, Stockholm, Sweden. The study was also supported by the
Swedish Medical Research Council (Diary Nos. 8318 and 3875). The
authors thank Lise Cederström, nurse, and Elisabeth Ottenhall, secretary,
for their skillful assistance.
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Characteristics in Patients with Schizophrenia
Lena Flyckt, Jörgen Borg, Kristian Borg, Tor Ansved, Gunnar Edman,
Lars Bjerkenstedt, and Frits-Axel Wiesel
Background: In a previous study of motor unit properties
in patients with schizophrenia, muscle fiber histologic and
electrophysiologic abnormalities were observed. The
present study was designed to compare patients with
schizophrenia with healthy control subjects with regard to
muscle fiber histology and motor unit function. A second
objective was to relate these variables to clinical
characteristics.
Methods: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSMIII-R) and 27 matched control subjects were included in
the study. Muscle biopsies were performed either in m.
tibialis anterior or m. vastus lateralis. Electromyographic
recordings (macro EMG) were made from the m. tibialis
anterior motor units. Psychiatric ratings included the
PANSS and extrapyramidal side effects.
Results: Seven of the muscle biopsy specimens from the
patients and one from the control subjects were classified
as abnormal (p 5 .049). The most frequent abnormality
was atrophic muscle fibers. Eight patients and no control
subjects exhibited pathological macro EMG (p 5 .032).
The findings were present in chronic as well as in
first-episode patients with schizophrenia.
Conclusions: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle
biopsy or the macro EMG investigations. The results
indicate that either a common pathologic process or
different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane
function. Biol Psychiatry 2000;47:991–999 © 2000 Society of Biological Psychiatry
Key Words: Muscle biopsy, macro EMG, schizophrenia,
muscle fiber atrophy, fiber density, motor unit
From the Department of Psychiatry, Karolinska Institutet, Danderyds Hospital (LF,
GE, LB) and the Department of Clinical Neuroscience, Neurology, Karolinska
Hospital (JB, KB, TA), Stockholm, and the Department of Neuroscience,
Psychiatry, Uppsala University Hospital, Uppsala (F-AW), Sweden.
Address reprint requests to Lena Flyckt, M.D., FoUU, Department of Psychiatry,
Danderyds Hospital, S-182 88 Danderyd, Sweden.
Received May 28, 1999; revised November 2, 1999; accepted November 10, 1999.
© 2000 Society of Biological Psychiatry
Introduction
T
he evidence of neuromuscular abnormalities in
schizophrenia is extensive. The type of abnormalities
range from skeletal muscle fiber changes (Meltzer and
Crayton 1975; Ross-Stanton et al 1980), alterations of
a-motoneuron excitability (Crayton et al 1977a), increased
motor unit fiber densities (Crayton et al 1977b; Crayton
and Meltzer 1979), and increased branching of terminal
motor nerves (Meltzer and Crayton 1974b; Ross-Stanton
and Meltzer 1981) to elevated levels of muscular enzymes
(Meltzer and Crayton 1974a; Zweig et al 1981). The
nature of the neuromuscular changes in patients with
schizophrenia is far from clear, but most studies have
concluded that they are secondary to neurogenic processes
of either central or peripheral origin (Borg et al 1987;
Crayton et al 1977a, 1977b; Crayton and Meltzer 1979;
Meltzer and Crayton 1974b, 1975; Ross-Stanton and
Meltzer 1981; Ross-Stanton et al 1980).
In the studies by Meltzer and coworkers, muscle fiber
abnormalities including atrophic fibers, “type-grouping,”
“central core fibers,” and “ring fibers” were found in about
half of the psychotic patients (Meltzer 1972; Meltzer and
Crayton 1975). In healthy controls subjects, muscle fiber
abnormalities were found in two of 34 cases (6%) (Meltzer
et al 1976). Similar abnormalities have been found in
patients with psychotic mood disorders, indicating that
they are not specific to schizophrenia (Meltzer 1973).
Thus, these findings may be associated with the occurrence of psychotic symptoms rather than a categorical
diagnosis. In a study of schizophrenic patients by Borg and
coworkers (1987), the muscle biopsy findings included
atrophic fibers, central nuclei, “moth-eaten fibers,” “ring
fibers” fiber splitting, and subsarcolemmal glucogen droplets. Neuroleptic medication could not explain the observed findings because they were also present in neuroleptic-free patients. The histologic changes observed have
been described in neurogenic as well as myogenic disorders. Because of the nonspecific nature of the muscular
changes, other concurrent findings must be considered to
better understand its causal connections. Thus, electrophysiologic investigations of single motor unit properties
0006-3223/00/$20.00
PII S0006-3223(99)00295-4
992
L. Flyckt et al
BIOL PSYCHIATRY
2000;47:991–999
demonstrated impaired distal impulse propagation,
whereas the axonal conduction velocity and refractory
period were normal, indicating a peripheral nerve involvement in the patients with schizophrenia (Borg et al 1987).
The findings of neuromuscular changes in patients with
schizophrenia are intriguing and deserve further exploration to find possible pathophysiologic mechanisms. The
aim of this study was to evaluate the hypothesis that
muscle fiber abnormalities are secondary to loss of distal
neural influence in patients with schizophrenia. The novel
approach to this question was the inclusion of patients
with first-episode schizophrenia, as well as the use of the
macro electromyographic (EMG) method because of its
ability to discern collateral sprouting, a sign of neuropathy, and thereby disentangling primary or myogenic
muscle fiber abnormalities from those secondary to distal
neuropathy. Another aim was to investigate the relationship between motor unit properties and clinical
characteristics.
Table 1. Sociodemographic and Clinical Characteristics of
Schizophrenic Patients and Healthy Control Subjects
Variable
Patients
(n 5 27)
Control
subjects
(n 5 27)
15 (56%)
12 (46%)
15 (56%)
12 (44%)
32.7
6.31
21– 45
32.2
7.23
21– 47
20.5
12.0
2–96
0.0
0.0
0–0
58.2
30.0
4 –192
0.0
0.0
0–0
259.4
200.0
100 – 800
0.0
0.0
0–0
Clinical Measures
Gender
Male
Female
Age (years)
Mean
SD
Range
Duration of schizophrenic
symptoms (months)
M
Md
Range
Duration of medication (months)
M
Md
Range
Neuroleptic medication (daily
dosage in equivalents of
chlorpromazine)
M
MD
Range
PANSS
Positive symptoms
M
SD
Range
Negative symptoms
M
SD
Range
Total symptoms
M
SD
Range
ESRS (observed symptoms)
Parkinsonism
M
SD
Range
Akathisia
M
SD
Range
Tardive dyskinesia
M
SD
Range
Dystonia
M
SD
Range
GAF score
M
SD
Range
The symptoms of illness were rated according to the Positive and
Negative Syndrome Scale (PANSS; Kay et al 1987). The Global
PANSS, Positive and Negative Syndrome Scale; ESRS, Extrapyramidal Symptom Rating Scale; GAF, Global Assessment of Functioning scale.
Methods and Materials
Subjects
Patients with schizophrenia were consecutively recruited on
admission to a psychiatric clinic in Stockholm. To be included,
the patients had to meet the DSM III-R (American Psychiatric
Association 1987) criteria for schizophrenia and be between 18
to 45 years of age. A clinical diagnostic interview and the
Structured Clinical Interview for the DSM-III-R (SCID; Spitzer
et al 1987) were performed independently by two clinicians (GE
and LF). Twenty-seven patients gave their informed consent to
enter the study. Twelve of these were experiencing their firstepisode of schizophrenia, and 15 were patients with chronic
schizophrenia. The two clinicians (GE and LF) agreed in their
diagnosis in 26 of 27 cases (96%). In the case of disagreement,
consensus was reached after consultation. If a first-episode
patient had less than a 6-month history of illness, he or she was
followed up to confirm the diagnosis of schizophrenia. For each
of the included patients, one healthy control subject with matching age and gender was selected from a group of 55 normal
individuals (Table 1). The exclusion criteria for patients and
control subjects were a history of drug abuse, head injury, or any
neurological or serious somatic disease. All subjects were asked
about their physical activity and dietary habits, and those
considered aberrant were not included (e.g., top-level athletes,
binge or anorectic eating habits, vegetarians, allergy to certain
foods). Control subjects were excluded if they filled the criteria
for a psychiatric diagnosis (DSM-III-R) or had a family history
in first- or second-degree relatives of psychiatric illnesses. There
was no overlap between the subjects in the present study and the
study by Borg et al (1987).
14.9
5.23
7–26
7.8
1.16
7–11
19.4
6.63
9 –33
8.5
1.50
7–12
68.5
14.44
48 –96
34.6
3.59
30 – 44
12.9
7.02
3–36
1.9
3.13
0 –12
0.8
1.01
0–4
0.0
0.00
0–0
1.8
3.36
0 –11
0.2
0.58
0 –2
1.7
3.52
0 –13
0.0
0.00
0–0
50
12.0
20 –70
84
4.0
75– 89
Neuromuscular Abnormalities in Schizophrenia
Assessment of Functioning scale (GAF; American Psychiatric
Association 1987) was used to rate the level of functioning. The
Extrapyramidal Symptom Rating Scale (ESRS; Chouinard et al
1980) was used to rate side effects of neuroleptic medication. All
clinical ratings were made when the subject entered the study.
Because it was not always possible to perform the muscle biopsy
in the acute phase, the clinical ratings occasionally preceded the
biopsy by some weeks. Responsiveness to neuroleptic medication was based on a global rating of recovery (“yes, no, partly”)
made by a trained clinician (LF) about 6 months after the
initiation or adjustment of neuroleptic medication.
Neuroleptic Medication
Two of the first-episode schizophrenic patients had never taken
medication for their illness, and one of the chronic patients had
been off neuroleptic medication for 6 months. Twenty patients
were on conventional neuroleptics, and four were on clozapine.
The mean dosage (equivalents of chlorpromazine; Beckman and
Laux 1990) and mean duration of neuroleptic medication at the
time for the muscle biopsy are shown in Table 1. Additional
medication for day and night sedation (benzodiazepines) was
allowed and a few patients were on low doses of oxazepam and
nitrazepam.
Muscle Biopsy Procedure
Muscle biopsy was performed in patients (n 5 26) and control
subjects (n 5 26) either in m. tibialis anterior (TA) or in m.
vastus lateralis (VL) using the percutaneous conchotome method
(Radner 1962). The reason for the choice of two muscles instead
of one was to increase the sites of investigation and thereby
increase the representativity. The muscle biopsies from the
patients were performed in the same muscle as the matching
control subject. The biopsy material was immediately frozen in
Freon 22, which was kept at its melting point (2190°C) by liquid
nitrogen, and then placed in a freezer at 275°C until further
processed. Sections of 10 –15 mm were cut in a cryostat operating
at 225°C. One patient dropped out of the study because of
noncompliance.
Histochemical and Morphometrical Techniques
Cross-sections were stained with haematoxylin-eosin and modified tricrome (Engel and Cunningham 1963) for myofibrillar
ATPase (mATPase; Padykula and Herman 1955) and NADH-TR
(Scarpelli et al 1958). The classification of muscle fiber types
was based on their mATPase staining characteristics, as described by Brooke and Kaiser (1970).
The cross-sectional areas of the muscle fibers were measured
directly from the microscope via a CCD camera (Hamamatsu
C3077, Hamamatsu Photonica KK, Japan) connected to an
image-analysis processor (Vidas, Kontron Bildanalyse, GmbH,
Munich). Measurements were made on 100 type I and type II
fibers from each biopsy specimen. The muscle fibers were
selected from a central part of the biopsy specimen considered
not to contain artifacts. If the total number of fibers of respective
type was smaller than these numbers, then all fibers of that type
were measured.
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2000;47:991–999
993
Classification of Histopathologic Changes in
Muscle Biopsies
The muscle biopsies were blindly classified as normal and
abnormal by two neurologists (KB and TA). The biopsy was
classified as abnormal if the specimen contained any of the
following changes: central nuclei in more than 3% of the fibers,
more than eight atrophic muscle fibers, splitting phenomena,
inclusion bodies, more than three irregular staining of formazan
granules, and the presence of type grouping. The criteria of the
classification are based on the work of Mastaglia and Detchaut
(1992). A neurologist (TA), blinded to the diagnosis, estimated
modal distributions of fiber areas by inspection of fiber area
histograms made for each subject.
Macro EMG
The first 22 patients and 10 control subjects included in the study
were investigated with macro EMG. Electromyographic recordings were made from the m. tibialis anterior motor units by
macro EMG needle electrodes (Medelec 17915) and displayed
on a Medelec oscilloscope (MS92B no 67127) connected to a
microcomputer (Victor PCII). The needle electrode is a modified
single fiber EMG electrode. One single fiber recording was
registered from a side port on the needle electrode with an uptake
area of one or two muscle fibers. The single fiber action potential
was used to trigger the recordings of simultaneous electrical
activities picked up by the electrode shafts from “all” muscle
fibers belonging to the same motor unit. By averaging during
slight voluntary activation, the electric activity was obtained as
the macro EMG action potential.
Recordings were made from motor units recruited at slight
voluntary activation, a prerequisite for the analysis. Because one
of the patients was unable to keep a slight and stable activation,
the subject was excluded. Macro EMG recordings were analyzed
according to Stålberg (1990) using Stålberg Intersoft program
Macro 4.1 1992. Data collected from the patients were compared
with published age-related reference data from a previous study.
(Stålberg and Fawcets 1982) and 10 age-and gender-matched
control subjects from the present study. Two or more motor unit
potentials with an amplitude, area, or median value outside the
defined range (6 2 SDs) was considered pathological (Stålberg
1990; Stålberg and Fawcets 1982). The fiber density was defined
as the mean number of single muscle fiber action potentials at
each of the 20 macro EMG recording sites according to established criteria (Stålberg and Trontelj 1979).
Statistics
Clinical data were summarized using conventional descriptive
statistics: means, standard deviations, median ranges, and frequencies. Dichotomous variables were analyzed with the chisquare method or Fisher’s exact test, two-tailed. Parametric
Student’s t test was applied for group-wise comparisons of
continuous variables. In case of skewed distributions with
outliers, nonparametric Mann–Whitney U test was applied in the
group comparisons (e.g., means of cross-sectional fiber areas and
daily doses of equivalents of chlorpromazine) and Kendall’s rank
994
BIOL PSYCHIATRY
2000;47:991–999
Figure 1. Cryostat cross-section of muscle biopsy, stained with
haematoxylin-eosin, from a schizophrenic patient. Three angulated atrophic muscle fibers are present in the center. Original
magnification 3250.
correlation for relationships between variables. A value of p ,
.05 was considered to be statistically significant. Because of the
low power of the comparisons, no correction of multiple comparisons was made so as not to increase the risk of committing
type II errors. By making planned comparisons, the increased
risk of type I errors was taken into account.
Results
L. Flyckt et al
pathological macro EMG recordings (Fisher’s exact test 5
0.032; Table 3). Figure 2 illustrates the recordings from
two motor units, one with a larger amplitude and area
(Figure 2A) and the other with an amplitude and area
within the normal range (Figure 2B). The upper traces
show the averaged single fiber action potentials, and the
lower traces show the averaged macro EMG potentials.
Figure 3 depicts the amplitudes and areas from all 20
motor units recordings in two patients (A and B). Figure
3A shows the data from a patient with a shift of the motor
unit potentials toward the upper limit for amplitude and
area. Six motor unit potentials were outside the normal
range (indicated by the outer square border), and the
median value also was outside the normal range (indicated
by the inner square border). Figure 3B shows the corresponding data from a patient with ordinary motor unit
potential amplitudes and areas.
Fiber density (FD; i.e., the mean of the number of single
muscle fiber potentials at each recording site) was calculated for all patients and control subjects. In the eight
patients with pathological macro EMG motor unit potentials, fiber densities ranged from 1.1 to 2.0 (mean 5 1.4),
in the 13 patients with normal macro EMG from 1.1 to
1.9.(M 5 1.3), and in the control subjects from 1.1 to 1.7
(M 5 1.4). There were no significant differences in fiber
density among these groups.
Muscle Biopsy Findings
Histologic changes were found in seven patients and in
one control subject (Fisher’s exact test 5 0.049). The most
frequent abnormality in the patients was atrophic muscle
fibers scattered or in groups (Figure 1 and Table 2). On
ATPase staining, the atrophic fibers were of both type I
(slow twitch) and type II (fast twitch). Regarding other
abnormalities in modified trichrome and NADH-TR
stained sections such as vacuols, ring fibers, tubular
aggregates, subsarcolemmal glucogen droplets, and irregular staining of formazan granules, there were no significant differences between the biopsies from patients and
those of control subjects.
Mean muscle fiber areas of type I, type II a, or type II
b did not differ significantly between patients and control
subjects. No differences between patients and control
subjects in modal distributions of fiber area histograms
was observed. There was no significant difference in mean
fiber area between the patients classified as normal or
pathological in muscle fiber morphology.
Macro EMG
Macro EMG recordings were available from 20 motor
units in each of the 21 patients. According to the used
criteria (see Methods and Materials), eight of the schizophrenic patients and none of the control subjects exhibited
Relationships among Muscle Biopsy, Macro EMG,
and Clinical Characteristics
Seven of twenty-six patients exhibited muscle biopsy
abnormalities and 8 of 21 patients a pathological macro
EMG. Only three patients showed abnormalities in both
investigations [x2(1) 5 0.36, p 5 .550].
No relationship was found between symptoms of illness
and muscle biopsy abnormalities except in patients with
positive symptoms, especially delusions (Z 5 1.6657, p 5
.09). There were no significant differences between patients with and without muscle fiber abnormalities in the
daily dosage of neuroleptic medication, lifetime exposure
(months) to neuroleptic medication, GAF, or any of the
ESRS items. Patients who were experiencing their first
episode of schizophrenia (n 5 12) or who had a chronic
course (n 5 14) did not differ in muscle fiber morphology.
Three chronic and four first-episode schizophrenic patients had muscle fiber abnormalities. There was no
relationship between increased age or responsiveness to
medication and muscle biopsy findings (Table 2).
Patients with pathological and normal macro EMG did
not differ significantly in daily dosage (equivalents of
chlorpromazine), lifetime exposure (months) to neuroleptic medication, or responsiveness to neuroleptic medica-
Neuromuscular Abnormalities in Schizophrenia
995
BIOL PSYCHIATRY
2000;47:991–999
Table 2. List of Patient Characteristics
First
episode
Macro
EMG
Muscle
biopsy
Male
Male
Male
No
No
No
Pathologic
Pathologic
Pathologic
Normalb
Normalc
Pathologicb
Male
Male
Male
Male
Male
Male
Male
Male
Male
No
No
No
No
No
No
No
Yes
Yes
Pathologic
Normal
Normal
Normal
Normal
Pathologic
Normal
Pathologic
Normal
Normalc
Normalb
Normalc
Normalc
Normalc
Normalc
Normalc
Normalc
Pathologicc
Male
Male
Male
Female
Female
Female
Female
Female
Yes
Yes
Yes
No
No
No
No
No
Normal
Not done
Not done
Normal
Pathologic
Normal
Not done
Normal
Not done
Normalc
Pathologicc
Normalc
Pathologicb
Normalc
Normalc
Pathologicc
Female
Female
Yes
Yes
Normal
Normal
Normalc
Pathologicc
Female
Female
Female
Female
Female
Yes
Yes
Yes
Yes
Yes
Normal
Not done
Not done
Pathologic
Not done
Pathologicc
Normalc
Normalc
Normalc
Normalc
Gender
Type of muscle
fiber abnormality
Moth-eaten fibers,
I—atrophy
Scattered atrophic
fibers
I—atrophy
II–atrophy
II b—atrophy,
central nuclei
Scattered atrophic
fibers
II b—atrophy
GAF
Lifetime
exposure to
neurolepics
(months)
Equivalents of
clorpromazine
Response to
neuroleptic
medication
65
40
45
18
144
192
100
0d
175
Yes
Partly
No
49 (60)
173 (24)
120 (96)
67 (12)
23 (8)
47 (18)
132 (48)
7 (12)
16 (9)
50
37
40
45
45
50
65
53
20
48
36
120
63
12
27
120
7
16
325e
150
800e
350
200
200
375e
200
100
Partly
Partly
No
No
Yes
Partly
No
Yes
Yes
15 (12)
17 (12)
10 (9)
108 (24)
305 (2)
94 (12)
108 (12)
180 (6)
50
65
70
60
50
45
67
50
4
0
10
88
180
74
69
120
200
0f
150
200
350e
325
200
225e
Yes
No
No
Yes
No
Yes
Yes
Partly
19 (12)
56 (12)
70
50
16
12
150
250
Yes
Yes
8 (10)
127 (6)
12 (6)
7 (7)
2 (48)
35
35
40
65
45
8
20
12
4
0
200
500e
200
300
0f
Yes
Partly
Partly
Yes
n/a
Duration of
illness in
monthsa
31 (24)
168 (4)
192 (48)
EMG, electromyogram; GAF, Global Assessment of Functioning scale.
The figures indicate the time from the first psychiatric contact to the investigation. Figures within parentheses show the time from the onset of symptoms to the first
psychiatric contact.
b
The muscle biopsy was performed in the m. vastus lateralis.
c
The muscle biopsy was performed in the m. tibialis anterior.
d
The patient had been off medication for 6 months.
e
Atypical neuroleptic medication (clozapin).
f
The patients were neuroleptic naive.
a
tion. There were no significant differences between these
patient groups in age; in the PANSS, ESRS, or GAF
scores; or in whether the patients were first episode (n 5
7) or had a chronic course (n 5 14). Two first episode and
six chronic patients had pathological macro EMG.
Discussion
Neuromuscular abnormalities were found in 13 patients
(48%), either in the muscle biopsy or macro EMG investigations, in both chronic and first-episode schizophrenic
patients. The muscle biopsy findings in seven of the
patients included angulated atrophic muscle fibers, scattered or in groups. Atrophy is the most common response
of a muscle fiber to loss of neural influence. Angulated
small fibers, previously normal in size, are considered to
be the result of a neural degeneration and subsequent
atrophy. Scattered or randomly distributed fiber atrophy
may be present in the early phase of neural loss. These
findings are in accordance with the results from earlier
studies (Crayton et al 1977a, 1977b; Crayton and Meltzer
1979; Meltzer and Crayton 1975; Ross-Stanton et al 1980;
Ross-Stanton and Meltzer 1981).
In these earlier studies, distal muscle groups were
investigated (m peroneus brevis for the muscle biopsy and
m flexor digitorum longus for EMG studies), but in our
study, more proximal muscles were studied (m tibialis
anterior and m vastus lateralis for the muscle biopsy and m
tibialis anterior for the macro EMG). The findings seem to
be present regardless of the site of investigation, indicating
996
L. Flyckt et al
BIOL PSYCHIATRY
2000;47:991–999
Table 3. Macro Electromyographic Data in Schizophrenic Patients and Matched Control Subjects
Amplitude
(mV)
Subject
Area
(mV 3 ms)
Fiber density
(n)
Classification
Gender
P
C
P
C
P
C
P
C
Malea
Female
Male
Male
Male
Male
Male
Femalea
Femalea
Malea
Female
Male
Malea
Male
Male
Femalea
Female
Femalea
Male
Female
254
278
239
298
479
478
532
307
254
239
181
176
181
187
195
181
185
210
141
170
186
190
190
1709
1287
1554
1345
1988
1936
2331
2079
1279
1020
906
684
960
955
1191
1154
1130
1258
663
748
1207
1164
837
1.3
1.1
1.2
1.2
1.1
2.2
1.5
1.8
1.3
1.3
1.3
1.1
1.3
1.4
1.4
1.4
1.4
1.9
1.5
1.4
1.6
1.1
1.6
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Pathol
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
268
257
199
186
215
156
184
1450
968
972
1018
1001
810
1041
1.7
1.2
1.3
1.4
1.6
1.5
1.4
Normal
Normal
Normal
Normal
Normal
Normal
Normal
P, patient; C, control subject.
a
Indicates a first-episode schizophrenic patient.
that the peripheral motor neurons and skeletal muscles are
affected throughout the body.
Pronounced physical inactivity may result in muscle
fiber atrophies (Edström and Grimby 1986; Houston et al
1979; Lindboe and Platou 1982). If the muscle fiber
atrophies among the patients in our study were caused by
inactivity, primarily the type 2 b fibers would have been
affected (Houston et al 1979), but atrophies were found in
all types of fibers. Thus, inactivity did not seem to be the
reason for the findings. In a study by Borg et al (1987) the
muscle biopsy findings included atrophic fibers, central
nuclei, and “moth-eaten fibers,” indicating loss of lower
motor neurons in accordance with our study. We did not
replicate the findings of vacuols, ring fibers, tubular
aggregates, subsarcolemmal glucogen droplets, and irregular staining of formazan granules, however. In our study,
about half of the patients were women and half were
experiencing their first episode of schizophrenia; in the
study by Borg et al (1987), there were no women and only
one patient was first episode. Studies have indicated
gender-related differences in muscle fiber morphology,
although this aspect was not observed in our study
(Glenmark et al 1992). Thus, the large proportion of
first-episode schizophrenic patients in our study seems to
be the most likely reason for the different findings.
The macro EMG recordings were pathological in 8 of
21 patients. The motor unit potentials had increased
amplitude and area compared with data from age- and
gender-matched control subjects, whereas fiber densities
did not differ. The interpretation of the abnormal macro
EMG data must consider factors affecting the muscle
fibers, as well as the peripheral and central neurons
(Stålberg 1990).
Muscle fiber hypertrophy may cause an increase of the
motor unit potential (Stålberg 1990); however, no hypertrophic fibers were found in the biopsies of the schizophrenic patients. Other factors have to be considered,
including those influencing the muscle fiber action potential (E. Stålberg, personal communication). Thus, disturbed muscle fiber membrane function may be consistent
with an increase of the macro EMG potential and retained
fiber density.
Increased fiber density, a sign of denervation and
reinnervation by collateral sprouting, has been described
previously in studies of psychotic patients (Crayton et al
1977b; Meltzer and Crayton 1974a; Ross-Stanton and
Meltzer 1981). The patients in these studies exhibited
different psychotic conditions, however; our study included a large number of first-episode schizophrenic
patients, a variable not previously investigated in relation
to fiber density. Therefore, it is possible that the differences in fiber density between the studies may indicate a
progress in motor unit pathology with the duration of
illness. We did not find any relationship between the
disease duration and motor unit abnormalities, however.
Moreover, muscle fiber abnormalities were found in four
Neuromuscular Abnormalities in Schizophrenia
BIOL PSYCHIATRY
2000;47:991–999
997
Figure 2. Examples of electromyogram (EMG) recordings
showing the average single muscle fiber potential (upper tracings) and macro EMG potential (lower tracings) of two motor
units (A and B). The macro EMG potential amplitude and area
were (A) above the normal range for one motor unit and (B)
within the normal range for the other.
first-episode schizophrenic patients, and pathological
macro EMG were found in two first-episode schizophrenic
patients, demonstrating that the changes in motor unit
properties begin in the early course of schizophrenia and
are not the result of a chronic course. Differences between
the results of the two studies may be attributablex to
contrasting methods (single fiber EMG vs. macro EMG),
different patient samples (other psychotic conditions vs.
schizophrenia), or both.
Loss of lower motor neurons with a compensatory,
collateral reinnervation might cause an enlargement of the
macro EMG motor unit potentials; however, there was no
relationship between the macro EMG and the muscle
biopsy findings. Further, the fiber density did not differ
between patients with and without increased action potentials. This argues against a loss of lower motor neurons. A
selective loss of low-threshold, type I motor units may be
consistent with increased macro EMG potentials and
normal fiber density, but the muscle biopsy data did not
support that interpretation. Thus, the present electromyographical data do not permit any conclusion about a loss of
lower motor neurons.
The possibility of a disturbed central activation must
also be considered. In normal subjects, low threshold
motor units have smaller motor unit action potentials than
do high-threshold motor units (Milner-Brown et al 1973;
Stålberg 1990). If there is a changed central activation
pattern with an earlier recruitment of larger motor units in
schizophrenic patients than in normal subjects, it might
explain the observed macro EMG changes. This might
then be attributable to a primary disease process affecting
both the central and peripheral nervous system.
The fact that the histologic abnormalities were found in
some but not all patients, as well as the low concordance
between the muscle biopsy and macro EMG findings may
be caused by a high rate of false negative muscle biopsy
specimens. In our study, the site of investigation included
Figure 3. Macro electromyogram recordings from two patients
with (A) pathological and (B) normal motor unit potential
amplitude and area values. The boxes show the 20 single motor
unit values, and the crosses show the median of these. The outer
square border indicates the normal range of motor unit potentials,
and the inner square border indicates the normal range of the
median value from an age-matched healthy reference population
(Stålberg and Fawcets 1982).
two different muscle groups; however, it is not possible to
eliminate the false-negative problem because there are
ethical issues associated with multiple biopsies in the same
patient. If the lack of concordance is genuine, however, the
interpretation may be that the neuromuscular systems—
both central and peripheral—are affected at different
levels by one common or several underlying factors, but
the processes have reached different stages.
Neuromuscular abnormalities may be connected to
disease-related factors, such as clinical characteristics and
neuroleptic medication; however, no relationship to symptoms, duration of illness, or function were found. Furthermore, the duration, side effects, and dosage of neuroleptic
medication were not related to the neuromuscular results.
In a previous study, of the m. tibialis anterior, drug-free
patients exhibited the same neuromuscular pathology as
those on neuroleptic drugs (Borg et al 1987). This indicates the neuromuscular changes are not related to the
symptoms, a chronic course or neuroleptic medication.
In conclusion, our data add to the accumulating number
of observations regarding motor-system disturbances on
multiple levels in schizophrenia, corresponding to previous suggestions by Meltzer and Crayton (1974a, 1975). It
also provides new insights, however. The neuromuscular
findings seem to be present in first-episode schizophrenic
patients, possibly in skeletal muscle groups throughout the
body. The combination of findings, that is, an increased
998
BIOL PSYCHIATRY
2000;47:991–999
amplitude and area of the muscle fiber action potential
together with a retained fiber density, point to changes in
the electrophysiological properties of the cell membrane.
Furthermore, the lack of concordance between findings
indicates that the pathophysiologic processes may operate
independently at different levels. Looking for a possible
factor in common, one may speculate about relation to the
observations of increased phospholipase A2 activity in
blood cells (Ross et al 1997), regarded as evidence of an
increased breakdown of cell membranes. This also seems
to take place in the brain, as indicated by reduced levels of
phosphomonesters and increased levels of phosphodiesters
in schizophrenic patients, determined by magnetic resonance spectroscopy (Pettegrew et al 1991). An altered cell
membrane composition and function in schizophrenia, as
previously suggested (Horrobin 1998; Wiesel and
Bjerkenstedt 1996), may be consistent with the neuromuscular findings in the present study.
This study was supported financially by the North-East Health Care
district, Stockholm, Sweden. The study was also supported by the
Swedish Medical Research Council (Diary Nos. 8318 and 3875). The
authors thank Lise Cederström, nurse, and Elisabeth Ottenhall, secretary,
for their skillful assistance.
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