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Brain glucose metabolism in violent psychiatric patients: a preliminary study
PSYCHIATRY RESEARCH NEUROIMAGING Psychiatry Research: Neuroimaging 61 (1995) 243-253
Brain glucose metabolism in violent psychiatric patients: a preliminary study Nora D. Volkow *a'b, Lawrence R. Tancredi b, Cathel Grant c, Hampton Gillespie c, Allan Valentine c, Nizar Mullani d, Gene-Jack Wang a, Leo Hollister c aMedical Department, Brookboven National Laboratory, Upton, NY 11973, USA bDepartment of Psychiatry, State University of New York at Stony Brook, Stony Brook, NY 11794, USA CDepartment of Psychiatry, University of Texas Health Science Center, Houston, TX 77030, USA dDivisian of Cardiology, University of Texas Health Science Center, Houston, TX 77030, USA Received 3 June 1994; revision received 6 February 1995; accepted 13 March 1995
Abstract
Positron emission tomography with ~SF-deoxyglucosewas used to evaluate regional brain glucose metabolism in eight normal subjects and eight psychiatric patients with a history of repetitive violent behavior. Seven of the patients showed widespread areas of low brain metabolism. Although the location of the abnormal regions varied among patients, they showed significantly lower relative metabolic values in medial temporal and prefrontal cortices than did normal comparison subjects. These regions have been implicated as substrates for aggression and impulsivity, and their dysfunction may have contributed to the patients' violent behavior.
Keywords: Positron emission tomography; intermittent explosive disorder; Antisocial personality; Schizophrenia; Frontal lobe; Temporal lobe
1. Introduction Investigation of the neurochemical and neuroanatomical mechanisms underlying criminal behavior is complicated by the complexity of interactions between environmental and biological variables in the emergence of violent behavior. Studies of violent behavior have concentrated on * Corresponding author, Medical Department, Bldg. 490, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. Tel: +1 516 282-3335; Fax: +1 516 282-5311; E-mail: [email protected]
the influence of either cultural and socially learned experiences (Turner et al., 1981) or abnormal brain function (Lewis et al., 1986) and genetics (Ellis, 1982). These categorical approaches have been unsuccessful in explaining the mechanisms underlying purposeless, repetitive violent behavior. Although one could conceive of situations in which the causes of violent behavior would be predominantly environmental (e.g., terrorism) or predominantly biological (e.g., as part of temporal lobe epilepsy) (Pincus, 1981; Wieser, 1983), for most cases of repetitive violence, the behavior is most likely the result of interactions among the ex-
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ternal environment, learned behaviors, and biological characteristics of the subject's brain. Among the biochemical variables associated with excessive aggressive behavior are high testosterone levels (Conner et al., 1969; Steklis et al., 1985; Christiansen and Knussmann, 1987) and decreased serotonin activity in the brain (Brown et al., 1979, 1982; Raleigh et al., 1980, 1986; Chamberlain et al., 1987; Higley et al., 1992). In the brain, the limbic regions - - in particular, the amygdala and the mesial temporal cortex - - have been implicated as neuroanatomical substrates for aggressive behavior (Rosvold et al., 1954; Kling et al., 1979). Because of these associations, various studies have been done to examine whether repetitive violent offenders have functional brain abnormalities that could explain their inappropriate, nonadaptive behavior (Mednick et al., 1982). Although most of these studies document a higher incidence of brain pathology in repetitive violent offenders than in matched comparison subjects (Poeck, 1969; Williams, 1969; Lorimer, 1972, Yeudall et al., 1982; Krieger, 1985; Adams and Victor, 1989), no specific brain abnormality has yet been identified. The lack of specific brain abnormalities in repetitively violent offenders could reflect such factors as the complexity of enviroumental and biological interactions leading to violence, the heterogeneity of violent behaviors (Mungas, 1983), and the multitude of neuroanatomical substrates which, if disrupted, can facilitate violent behavior (Goldstein and Huber, 1974; Eichelman, 1983; Albert and Walsh, 1984). It could also reflect, however, the lack of evaluation techniques with the sensitivity and specificity to accurately locate the neuroanatomical dysfunction in these patients. With the availability of new functional brain-imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (MRI) it is now possible to evaluate regional brain dysfunction with a higher sensitivity and accuracy than was possible with previously available techniques (Fowler and Wolf, 1991; Volkow and Tancredi, 1992). Thus, functional brain-imaging techniques may help to delineate brain substrates involved in violent behaviors (Tancredi and Volkow, 1992). In a preliminary PET study in four violent pa-
tients (Volkow and Tancredi, 1987), we showed decreased metabolic activity in frontal and left temporal cortex. A more recent PET study done in a group of subjects who had committed or attempted to commit a murder reported abnormalities in prefrontal cortex which the investigators implicated as a predisposing factor for the violent behavior of these subjects (Raine et al., 1994). An association between aggressive behavior and decrements in metabolism in orbitofrontal regions was documented in a PET study done in patients with personality disorders and "aggressive impulse difficulties" (Goyer et al., 1994). G-eneralizability of these frontal abnormalities to other groups of violent patients requires further investigation. The current study investigates regional brain metabolic abnormalities in a group of psychiatric patients with a history of frequent violent behavior. On the basis of our previous results (Volkow and Tancredi, 1987), we hypothesized that repetitive violent offenders would have widespread metabolic derangements and that they would have significantly lower metabolic activity in frontal and temporal cortices than normal comparison subjects. 2. Methods 2.1. Subjects Violent patients. Eight inpatients (mean age : 34 years, SD : 11) from the State Psychiatric Hospital in Harris County (Houston, TX) who fulfilled DSM-III-R diagnostic criteria for intermittent explosive behavior or for antisocial personality disorder (American Psychiatric Association, 1987) were studied. We selected subjects who had a past history of repetitive violent behavior characterized by its purposelessness and for whom their violent behavior had led to legal arrest. Purposelessness was defined when an act was performed without a desire to achieve a specific goal. Most of the violent acts were described by the patients either as impulsive behaviors or as intense aggressive responses. Three of the patients had an additional DSM.III-R diagnosis of schizophrenia (n = 2) or schizoaffective disorder (n = 1). None of the subjects had a past or present history of affective disorder. Though most of the patients used drugs of abuse once or twice a week, they were excluded if they had a past or present history of drug dependence (except for nicotine and caffeine). Patients
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Table 1 Clinical and demographic characteristics of violent patients Subject
Age (years)
Diagnosis
Violent behavior
Medication
i 2 3
51 36 31
lED lED lED, schizophrenia
Physical assault to self and others Homicide, self-mutilation Stabbed parents and girlfriend, self-mutilation
None None Haloperidol, 5 rag, p.o., b.i.d.
4
36
lED
None
5 6
26 26
7
24
lED lED, schizophrenia APD
Frequent fights, attempted homicide, violence exacerbated by alcohol Physical assault, homicidal ideation Physical assault, destructive behavior
8
27
IED,
schizoaffective disorder
Physical assault, homicidal ideation, rape of children Homicide, reports pleasure in killing
None Haloperidol, 5 mg, p.o., b.i.d. None
Thioridazine, 25 mg
Note. IED, intermittent explosive disorder; APD, antisocial personality disorder.
were also excluded if they had a history of neurological illness or head trauma leading to loss of consciousness. Because of the difficulties in managing their violent behavior, three of the patients had to be placed on psychoactive medication before the PET study. Table 1 provides clinical and demographic characteristics of the patients. Except for the three patients who were being treated with neuroleptics, none of the other subjects were receiving medications at the time of study. Normal subjects. Eight right-handed males (mean age = 32 years, SD = 7), all medically healthy and with no past or present history of violent behavior, formed the comparison group. Subjects were excluded if they had a past or present history of psychiatric or neurological disease, or if they were dependent on addictive drugs (except for nicotine and caffeine). Presence or absence of psychiatric illness was assessed with mental state and psychiatric history evaluations performed by one of the investigators (N.D.V., C.G., L.T.). None of the comparison subjects were taking medications at the time of study.
(Mullani et al., 1984). An initial transmission scan was obtained using a ring filled with ~gallium (200 million events were collected) to correct for attenuation. In preparation for the emission scans, subjects had two catheters implanted, one in an antecubital vein for radiotracer injection and another in a radial artery for plasma sampling to quantitate glucose and lSF-deoxyglucose (FDG) concentrations. Emission scans were obtained 35-55 min after injection of 6-8 mCi of FDG. Plasma samples were obtained manually, every 30 s for the first 3 min, every minute for the next 7 min, every 5 min for the next 15 rain, and at 15 min thereafter. During the FDG uptake period as well as during the scan, the subjects remained lying in a supine position in the bed of the PET camera with eyes open, ears unplugged, in a dimly lit room with noise kept to a minimum. No stimulations were used during the study. Subjects were requested to lie still during the FDG uptake and scanning period. An investigator remained by the side of the patients to ensure their compliance and that they did not fall asleep.
2.2. Scans PET scans were obtained using the TOFPET camera (full-width/half-maximum = 1.2 cm)
2.3. Image analysis Regions of interest (ROIs) were drawn directly on the PET image by one of the investigators
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31.1). Volkow et al. / Psychiatry Research: Neuroimaging 61 (1995) 243-253
LF PRE
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Fig. 1. Template for the location of regions of interest used in the analysis of metabolic images. L, left; R, right; PR, prefrontal; F, frontal; P, parietal; TM, temporal medial; TP, temporal posterior; OC, occipital; BG, basal ganglia; THL, thalamus; CBL, cerebellum.
(N.V.) without knowledge of the subject's diagnosis. A template that identified a total of 47 regions in the central seven sequential planes was used. The template was projected directly onto the metabolic images and was manually fitted into the individual image. A given anatomical region was identified in at least two sequential planes. Fig. 1 shows the location of the regions in the template. The 47 regions were grouped into 16 "composite" cortical, subcortical, and cerebellar regions which represented the weighted average of ROIs from different planes corresponding to the same anatomical structure. In addition, an approximate value for "whole brain" was obtained by averaging the activity in the seven central slices. Because the purpose of this investigation was to assess if there were regional brain defects in violent patients, we normalized the regional metabolic values to the whole brain metabolic activity. Differences between normal subjects and violent patients were tested for this relative measure with unpaired t tests. The significance level for comparisons in brain regions for which it was hypothesized a priori that there would be decrements in metabolism in violent patients was set at P < 0.05. Bonferroni corrections for multiple comparisons were applied to differences in other brain regions. To determine whether there was a lateralized effect in the pattern of regional
abnormalities between the groups, a two-factor analysis of variance (ANOVA) (normal subjects vs. violent patients) with repeated measures for hemisphere (right and left) was performed. To assess whether there was a regional effect, a twofactor ANOVA (normal subjects vs. violent patients) with repeated measures for regions (prefrontal, frontal, parietal, medial temporal, temporal-posterior, and occipital) was performed. To obtain a quantitative estimate of the frequency of regional defects in the brains of violent patients, we obtained the z-transformed values for the regional measures using the regional means and standard deviations (SD) from the normal subjects. The number of regions that were 2 SD outside these z-transformed values was quantified for the normal subjects and the violent patients, and differences between groups were compared by X2 analysis. 3. Results Visual inspection of the images revealed relatively large hypometabolic areas in many of the brains of the violent patients but not in the normal comparison subjects. Figs. 2 and 3 show representative images for a normal subject and a violent individual (subject 7). This patient had decreased metabolic activity throughout various planes in
N.D. Volkow et al. / Psychiatry Research: Neuroimaging 61 (1995) 243-253
247
Fig. 2. Brain glucose metabolic image from a normal subject. Nine sequential planes from the top to the bottom of the brain are shown. The scale to the right represents the relative concentration of lSF-deoxyglucose. Images have been normalized to the highest value for the individual. Left side of the brain is at the right side of the image. Fig. 3. Brain glucose metabolic image from a violent patient. Note the marked relative decrease in glucose metabolism throughout the left hemisphere.
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N.D. Volkow et aL / Psychiatry Research: Neuroimaging 61 (1995) 243-253
1.40
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cO ¢yJ (D
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rr 0.80
0.60
RPR LPR
RF
LF
RP
LP RTM LTM RTP LTP FIDC LOC RBG LBG THL CBL
Fig. 4. Average values for relative measures of regional brain metabolism in normal subjects (black) and violent patients (striped). Significant differences between groups: a = e < 0.05; b = P < 0.01. Regions represent: L, left; R, right; PR, prefrontal; F, frontal; P, parietal; TM, temporal medial; TIP, temporal posterior; OC, occipital; BG, basal ganglia; THL, thalamus; CBL, cerebellum.
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||
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•i
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VIt
Fig. 5. Individual values for relative metabolism in fight and left prefrontal and medial temporal cortex for normal subjects (Nml) and violent patients (Vlt),
N.D. Volkow et al./Psychiatry Research: Neuroimaging 61 (1995) 243-233
249
Table 2 Relative metabolic values in normal subjects and violent patients with and without neuroleptic treatment in prefrontal and medial temporal cortex Region
Normal subjects
Right prefrontal Left prefrontal Right medial temporal Left medial temporal
Violent patients
SD
Mean
SD
Mean
SD
1.08 1.09 1.04 1.07
0.04 0.04 0.04 0.04
1.04 1.04 0.97 i .00
0.05 0.06 0.07 0.04
1.02 i .03 0.96 1.02
0.04 0.03 0.03 0.06
Table 3 Number of regions with values 2 standard deviations outside the regional normative data range
Prefrontal Frontal Parietal Medial temporal Posterior temporal Occipital Basal ganglia Thalamus Cerebellum Total
Drug-free (n = 5)
Mean
the left frontal, temporal, and parietal cortical regions. Comparison of relative metabolic values showed that the violent patients had significantly (P < 0.05) lower metabolism for left and right prefrontal regions, left frontal regions, and left and right temporal medial areas than the normal subjects (Fig. 4). Fig. 5 presents the individual values for the left and right prefrontal and medial temporal regions. To determine if the metabolic abnormalities were due to neuroleptic treatment, we separately tabulated the values for the prefrontal and medial temporal cortex for the violent patients with and without neuroleptic treatment along with the values for the normal subjects (Table 2). Pa-
Regions
Neuroleptic-treated (n = 3)
Normal subjects
Violent patients
Left
Right
Left
Right
0 0 0 0 0 1 0
0 I 0 0 0 0 0 0 0 2
4 3 2 6 3 2 3 I 1 38
3 3 ! 4 1 0 I
tients who were receiving neuroleptics were not responsible for the hypofrontality since prefrontal values were not lower in neuroleptic-treated patients than in drug-free patients. Both subgroups had lower values than normal subjects. Although a significant group effect was observed for the prefrontal (F = 7.5; df= 1, 14; P < 0.014) and for the medial temporal cortex (F - 31; df= 1, 14; P < 0.0001), there was no laterality x group interaction effect, indicating that the reductions in metabolism were present in both hemispheres. The analysis for regional effects (prefrontal, frontal, medial temporal, posterior temporal, parietal, and occipital) revealed a significant group x region interaction effect (F = 13; df= 5, 14; P < 0.0001) indicating a greater reduction in metabolism for prefrontal and medial temporal regions. Analysis of the z-transformed regional values revealed that seven of the eight violent patients had cortical areas of decreased relative metabolism in two or more of their brain images. This pattern was seen only for one of the brain images in two normal subjects. Comparison of the number of areas that were abnormal showed the violent patients had significantly (X2 = 35.72, P < 0.0001) more regions that were below 2 SD (38 regions) outside the z-transformed values than did the normal subjects (2 regions). Table 3 shows the location of these regional abnormalities in the normal subjects and in the violent patients. Although the most frequently abnormal regions were located in frontal and temporal areas, there were also abnormalities in parietal, occipital, and subcortical
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regions. Abnormalities occurred more frequently in the left than in the right hemisphere, but this difference was not statistically significant. 4. Discussion
This study documents abnormal regional brain metabolic activity in repetitively violent patients. Similar to our previous study (Volkow and Tancredi, 1987), the most frequently affected brain areas in the violent patients were the prefrontal and the temporal medial cortex. Both prefrontal and medial temporal brain regions have been frequently implicated in the pathogenesis of violent behavior in neurologic and psychiatric patients (Poeck, 1969; Williams, 1969; Lorimer, 1972; Yeudall et al., 1982; Krieger, 1985; Adams and Victor, 1989). As in our previous study (Volkow and Tancredi, 1987), the prefrontal cortex was found to be abnormal in this group of violent patients. Metabolic derangements in prefrontal cortex were similarly observed in individuals who had attempted or had committed a murder (Raine et al., 1994). Abnormalities in frontal metabolism have also been documented in patients with personality disorders with a history of aggressive behaviors (Goyer et al., 1994). The consistency of the findings of frontal hypometabolism in these four studies, each of which investigated subjects with different types of violent behaviors, would suggest that deficits in metabolism of frontal regions may underlie a predisposition for violence. However, decreases in frontal metabolism have also been documented in a wide variety of psychiatric and neurological disorders not associated with violence. It could be argued that frontal hypometabolism is a nonspecific finding common to many forms of cerebral pathology. The frontal cortex is histologically and functionally heterogeneous, and investigation of regions within the frontal cortex that are abnormal may start to reveal some specificity. It is also possible that what characterizes pathology for a given disease is not an abnormality in one brain region but rather the pattern of brain abnormalities. For example, while schizophrenic patients have been shown to have an hypofrontal pattern of metabolic activity, they also have subcortical metabolic
changes. For the present group of violent patients, the hypofrontality occurred in the presence of hypometabolism in medial temporal cortex. One could speculate that because the prefrontal cortex serves to control behavior (Luria, 1966), a lower threshold for the perception of anger secondary to abnormalities in medial temporal areas may be followed by a violent reaction in a subject who lacks an adequate frontal inhibitory control mechanism. Neurochemically, both impulsive and aggressive behaviors have been linked to decreased serotonin activity (Virkunnen et al., 1994a, 1994b). The prefrontal cortex sends efferents to both rostral and caudal raphe nuclei where most of the cells of origin of the serotonin system are located (Heimer, 1994); thus, it could be postulated that dysfunction of prefrontal regions disrupts serotonin activity in the brain. Because the prefrontal cortex is involved in the organization of behavior, abstraction, and consciousness (Luria, 1966), its disruption could also facilitate violent behavior indirectly by interfering with the individual's perception of the situation and with the understanding of ethical concepts as well as by decreasing the repertoire of alternative behaviors. Violent subjects were also found to have significantly lower metabolism in medial temporal regions compared with normal subjects. Due to the limited spatial resolution of the PET instrument used in the study, the medial region selected was relatively large and comprised insula, amygdala, hipoccampus, and uncus. These brain regions are known to play an important role in the regulation and expression of emotions including aggressive behaviors (Goldstein and Huber, 1974; Mirsky and Harman, 1974; Albert and Walsh, 1984). The temporal lobe circuits involved in aggression have testosterone neurons (Stumpf, 1980), and they also receive serotonergic innervation, both of which are postulated to modulate agonistic behavior (Albert and Walsh, 1984; Adams and Victor, 1989). The temporal medial cortex is neuroanatomically connected with other limbic structures, such as the hypothalamus, which have been directly associated with aggressive behaviors (Mark and Swelt, 1974). It is also neuroanatomically connected with cortical association areas and has been postulated to serve as a synap-
N.D. Volkow et al./ Psychiatry Research: Neuroimaging 61 (1995) 243-253
tic buffer between external reality and internal urges (Mesulam, 1985) that, if disrupted, could disturb the flexibility of the individual to respond appropriately to inner needs and environmental situations. Temporal metabolic abnormalities were not detected in the studies done on the subjects who had attempted or committed a murder (Raine et al., 1994). Discrepancies could reflect different experimental conditions; in the study of Raine et al., subjects performed the CPT test and were scanned while medication free, whereas for the current study subjects were scanned with no stimulation and three of them were receiving neuroleptic medication. However, discrepancies could also reflect differences between the subject groups. The study of Raine et al. selected subjects on the basis of a history of attempted or committed murder, whereas in the current study selection was based on a history of frequent violent behavior. Subjects in this investigation were inpatients in a psychiatric hospital; seven had a diagnosis of intermittent explosive disorder, and one of antisocial personality disorder. Thus, one could postulate that the discrepancy between the two studies may reflect the heterogeneity of violence and that findings may not be generalizable to "violent subjects," per se, but rather reflect abnormalities pertaining to a very specific subgroup of violent patients. Violent patients were characterized by a higher incidence of defects in brain areas that have been implicated as substrates for aggressive behavior, but it would be premature to attribute the patients' violent behavior to their brain abnormalities. Abnormalities in frontal and temporal cortical metabolism, it should be remembered, have also been documented in patients with no history of violent behavior (Volkow and Fowler, 1992). It is more likely that the brain abnormalities were a contributing factor that acted in conjunction with the environmental interactions and the past experience of the individual. Future studies comparing differences between violent patents with frontal and temporal abnormalities with patients with the same pattern of abnormalities but without a history of violence may enable investigators to understand better the circumstances under which these abnormalities facilitate violent behaviors.
251
Also, imaging studies on violent patients have been done mostly in subjects who were not violent at the time of the study. Future studies should be designed so that patients are assessed while on a mental state resembing that when they become violent. This could be achieved by using pharmacological challenges with psychoactive drugs that are known to facilitate violent behaviors (e.g., alcohol) and/or using stimulation paradigms that elicit anger (e.g., loud noise). Such activation studies may enable investigators to determine the extent to which particular brain regions are involved in the experience of anger and in the expression of violent behavior. They will also aid in determining whether the involvement of a given brain region is facilitatory or is one of inhibitory control. A limitation of this study was that three of the patients had an additional diagnosis of schizophrenia and were receiving neuroleptic medication at the time of the study. Hence, the abnormalities in these subjects are confounded by the disease process and the use of neuroleptics. Because neuroleptics have sometimes been shown to accentuate hypofrontality in schizophrenic patients, it could be argued that the hypofrontality in the violent patients was due to medication. However, there were no differences in frontal metabolism between neuroleptic-treated violent patients and their unmedicated counterparts, indicating that the hypofrontality was not a medication effect. The mechanisms underlying hypofrontality in this group of violent patients cannot be ascertained but are probably diverse, including head trauma, antipsychotic medication, substance abuse, and mental illness. Because patients were not studied with magnetic resonance imaging, it was not possible to determine the extent to which hypofrontality in these patients was associated with structural brain defects. Though patients were excluded if they had experienced trauma leading to loss of consciousness, it is possible that some patients may have lied about their histories, experienced memory lapses, or suffered from injuries that did not lead to loss of consciousness but nonetheless induced brain damage. The two groups of subjects were not comparable with respect to racial representation (violent group: 3 blacks, 2 Hispanics, and 3 Caucasians; comparison group: 1
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black, 1 Hispanic, and 6 Caucasians), but this difference is unlikely to have contributed to the findings. This study documents decrements in metabolic activity in prefrontal and medial temporal cortex in repetitive violent offenders. The consistency of the finding of frontal metabolic decrements in heterogeneous groups of violent subjects suggests that decreased frontal activity may facilitate, under appropriate circumstances, the emergence of violent or aggressive behaviors. The role that abnormalities in mesial temporal cortex play in the emergence of frequent violent behaviors requires further investigation. The increasing prevalence of violence in our society poses a sense of urgency for understanding the neuroanatomical substrates underlying violent behavior in humans. The search for causal links between violent behaviors and neuroanatomical defects has important scientific, therapeutic, social, and legal implications (Tancredi and Volkow, 1988; Mayberg, 1992); and its complexity should not deter investigation. Future studies evaluating more homogeneous groups of violent patients studied with stimulation paradigms designed to trigger violent or aggressive responses may enable investigators to start to understand the role that specific brain abnormalities play in the emergence of violent behaviors. Acknowledgments This research was supported in part by the U.S. Department of Energy under Contract DE-ACO276CH00016 and National Institutes of Health (AA 09481). The authors thank C. Wong and D. Patel for technical assistance. References Adams, R.D. and Victor, M. (1989) The limbic brain and the neurology of emotion. In: Principles of Neurology. McGraw Hill, New York. Albert, D.J. and Walsh, M.L. (1984) Neural systems and the inhibitory modulation of agonistic behavior: a comparison of mammalian species. Neurosci Biobehav Rev 8, 5-24. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. Brown, G.L., Ballenger, J.C., Minichiello, M.D. and Goodwin, F.K. (1979) Human aggression and its relationship to
cerebrospinal fluid 5-hydroxyindoleacetic acid, 3-methoxy-4hydroxyphenylglycol and homovanillic acid. In: Sandier, M. (Ed.), Psychopharmacology of Aggression. Raven Press, New York. Brown, G.L., Ebert, M.H. and Goyer, P.F. (1982) Aggression, suicide and serotonin: relationships to CSF amino metabolites. Am J Psychiatry 139, 741-746. Chamberlain, B., Ervin, F.R., Pihl, R.O. and Young, S.N. (1987) The effects of raising or lowering tryptophan levels on aggression in vervet monkeys. Pharmacol Biochem Behav 28, 503-510. Christiansen, K. and Knussmann, R. (1987) Androgen levels and components of aggressive behavior in men. Horm Behav 21, 170-180. Conner, R.L., Levine, S., Werthein, G.A. and Cununer, J.F. (1969) Hormonal determinants of aggressive behavior. Ann N Y Acad Sci 159, 760-776. Eicbelman, B. (1983) The limbic system and aggression in humans. Neurosci Biabehav Rev 7, 391-394. Ellis, L. (1982) Genetics and criminal behavior: evidence through the end of the 1970's. Criminology 20, 43-66. Fowler, J.S. and Wolf, A.P. (1989) New directions in positron emission tomography. In: Bristol, J.A. (Ed.), Annual Reports in Medicinal Chemistry. Vol. 25. Academic Press, San Diego, CA. Goldstein, M. and Huber, M.V. (1974) Brain research and violent behavior: a summary and evaluation of biomedical research on brain and aggressive behavior. Arch Neurol 30, 1-35.
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criminal court: an argument for caution. Commentary. J Nucl Med 33, 18N-25N. Mednick, S.A., Pollock, V., Volavka, J. and Gabrielli, W.F. 0982) Biology and violence. In: Weiner, W. (Ed.), Criminal Violence. Sage, London. Mesulam, M.M. 0985) Patterns in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization. In: Mesulam, M.M. (Ed.), Principles of Behaviaral Neurology. A. Davis Company, Philadelphia. Mirsky, A.F. and Harman, N. (1974) On aggressive behavior and brain disease - - some questions and possible relationships derived from the study of man and monkeys. In: Whalen, R. (Ed.), Neuropsychology of Aggression. Plenum Press, New York. Mullani, N.A., Gaeta, J., Yerian, K., Wang, W.H., Hartz, R.K., Philippe, E.A., Bristow, D. and Gould, K.L. 0984) Dynamic imaging with high resolution time of flight PET camera TOFPET. IEEE Trans Nucl Sci 31,609-613. Mungas, D. (1983) An empirical analysis of specific syndromes of violent behavior. J Nerv Ment Dis 171, 354-361. Pincus, J.H. (1981) Violence and epilepsy. N Engl J Med 305, 696. Poeck, K. (1969) Pathophysiology of emotional disorders associated with brain damage. In: Vinken, PJ. and Bruyn, G.W. (Eds.), Handbook of Clinical Neurology, Vol. 3: Disorders of Higher Nervous Activity. North-Holland, Amsterdam. Raine, A., Buchsbaum, M.S., Stanley, J., Lottenberg, S., Abel, L. and Stoddard, J. (1994) Selective reductions in prc-frontal glucose metabolism in murderers. Biol Psychiatry 36, 365-373. Raleigh, M.J., Brammer, G.L., Ritvo, E.R., Gcller, E., McGuir¢, M.T. and Yuwiler, A. (1986) Effects of chronic fenfluramine on blood serotonin, cercbrospinal fluid metabolites, and behavior in monkeys. Psychopharmacology 90, 503-508. Raleigh, M.J., Brammer, G.L., Yuwiler, A., Flannery, J.W. and McGuire, M.T. (1980) Serotonergic influences on the social behavior of vervet monkeys (Cercopithecus aethiops sabaeus). Exp Neurol 68, 322-334. Rosvold, H.E., Mirsky, A.F. and Pribram, K. (1954) Influence of amygdalectomy on social behavior in monkeys. J Comp Physiol Psychol 47, 173-178. Steklis, H.D., Brammer, G.L., Raleigh, M.J. and McGuire, M.T. (1985) Serum testosterone, male dominance, and ag-
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gression in captive groups of vervet monkeys (Cercopithecus aethiops sabaeus). Harm Behav 19, 154-165. Stumpf, W.E. (1980) Anatomical distribution of steroid hormone target neurons and circuitry in the brain. In: Motta, M. (Ed.), The Endocrine Functions of the Brain. Raven Press, New York. Tancredi, L. and Volkow, N.D. (1988) Neural substrates of violent behavior: implications for law and public policy. Int J Psychiatry Law 1i, 13-45. Tancredi, L.R. and Voikow, N.D. (1992) The mind/brain dichotomy studied with positron emission tomography: towards an integrative theory. Perspect Biol Med 35, 549-571. Turner, C.W., Fenn, R.M. and Cole, A.M. (1981) A social psychological analysis of violent behavior. In: Stuart, R.B. (Ed.), Violent Behavior: Social Learning Approaches to Prediction, Management and Treatment. Brunner/Mazel, New York. Virkkunen, M., Kailio, E., Rawlings, R., Tokola, R., Poland, R.E., Guidotti, A., Nemeroff, C., Bissette, G., Kalogeras, K., Karonen, S.-L. and Linnoila, M. (1994a) Personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry 51, 28-33. Virkkunen, M., Rawlings, R., Tokola, R., Poland, R.E., Guidotti, A., Nemeroff, C., Bissette, G., Kalogeras, K., Karonen, S.-L. and Linnoila, M. (1994b) CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry 51, 20-27. Volkow, N.D. and Fowler, J.S. (1992) Neuropsychiatric disorders: investigation of schizophrenia and substance abuse. Semin Nucl Med 22, 254-267. Volkow, N.D. and Tancredi, L. (1987) Neural substrates of violent behavior: a study with positron emission tomography. Br J Psychiatry 151,668-673. Wieser, H.G. (1983) Depth recorded limbic seizures and psychopathology. Neurosci Biobehav Rev 7, 427-440. Williams, D. (1969) Neural factors related to habitual aggression - - consideration of differences between those habitual aggressives and others who have committed crimes of violence. Brain 92, 503-520. YeudaU, L.T., Fromm-Auch, D. and Davies, P. (1982) Neuropsychological impairment of persistent delinquency. J Nerv Ment Dis 170, 257-265.
Brain glucose metabolism in violent psychiatric patients: a preliminary study Nora D. Volkow *a'b, Lawrence R. Tancredi b, Cathel Grant c, Hampton Gillespie c, Allan Valentine c, Nizar Mullani d, Gene-Jack Wang a, Leo Hollister c aMedical Department, Brookboven National Laboratory, Upton, NY 11973, USA bDepartment of Psychiatry, State University of New York at Stony Brook, Stony Brook, NY 11794, USA CDepartment of Psychiatry, University of Texas Health Science Center, Houston, TX 77030, USA dDivisian of Cardiology, University of Texas Health Science Center, Houston, TX 77030, USA Received 3 June 1994; revision received 6 February 1995; accepted 13 March 1995
Abstract
Positron emission tomography with ~SF-deoxyglucosewas used to evaluate regional brain glucose metabolism in eight normal subjects and eight psychiatric patients with a history of repetitive violent behavior. Seven of the patients showed widespread areas of low brain metabolism. Although the location of the abnormal regions varied among patients, they showed significantly lower relative metabolic values in medial temporal and prefrontal cortices than did normal comparison subjects. These regions have been implicated as substrates for aggression and impulsivity, and their dysfunction may have contributed to the patients' violent behavior.
Keywords: Positron emission tomography; intermittent explosive disorder; Antisocial personality; Schizophrenia; Frontal lobe; Temporal lobe
1. Introduction Investigation of the neurochemical and neuroanatomical mechanisms underlying criminal behavior is complicated by the complexity of interactions between environmental and biological variables in the emergence of violent behavior. Studies of violent behavior have concentrated on * Corresponding author, Medical Department, Bldg. 490, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. Tel: +1 516 282-3335; Fax: +1 516 282-5311; E-mail: [email protected]
the influence of either cultural and socially learned experiences (Turner et al., 1981) or abnormal brain function (Lewis et al., 1986) and genetics (Ellis, 1982). These categorical approaches have been unsuccessful in explaining the mechanisms underlying purposeless, repetitive violent behavior. Although one could conceive of situations in which the causes of violent behavior would be predominantly environmental (e.g., terrorism) or predominantly biological (e.g., as part of temporal lobe epilepsy) (Pincus, 1981; Wieser, 1983), for most cases of repetitive violence, the behavior is most likely the result of interactions among the ex-
0925-4927/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0925-4927(95)0267 I-J
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ternal environment, learned behaviors, and biological characteristics of the subject's brain. Among the biochemical variables associated with excessive aggressive behavior are high testosterone levels (Conner et al., 1969; Steklis et al., 1985; Christiansen and Knussmann, 1987) and decreased serotonin activity in the brain (Brown et al., 1979, 1982; Raleigh et al., 1980, 1986; Chamberlain et al., 1987; Higley et al., 1992). In the brain, the limbic regions - - in particular, the amygdala and the mesial temporal cortex - - have been implicated as neuroanatomical substrates for aggressive behavior (Rosvold et al., 1954; Kling et al., 1979). Because of these associations, various studies have been done to examine whether repetitive violent offenders have functional brain abnormalities that could explain their inappropriate, nonadaptive behavior (Mednick et al., 1982). Although most of these studies document a higher incidence of brain pathology in repetitive violent offenders than in matched comparison subjects (Poeck, 1969; Williams, 1969; Lorimer, 1972, Yeudall et al., 1982; Krieger, 1985; Adams and Victor, 1989), no specific brain abnormality has yet been identified. The lack of specific brain abnormalities in repetitively violent offenders could reflect such factors as the complexity of enviroumental and biological interactions leading to violence, the heterogeneity of violent behaviors (Mungas, 1983), and the multitude of neuroanatomical substrates which, if disrupted, can facilitate violent behavior (Goldstein and Huber, 1974; Eichelman, 1983; Albert and Walsh, 1984). It could also reflect, however, the lack of evaluation techniques with the sensitivity and specificity to accurately locate the neuroanatomical dysfunction in these patients. With the availability of new functional brain-imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (MRI) it is now possible to evaluate regional brain dysfunction with a higher sensitivity and accuracy than was possible with previously available techniques (Fowler and Wolf, 1991; Volkow and Tancredi, 1992). Thus, functional brain-imaging techniques may help to delineate brain substrates involved in violent behaviors (Tancredi and Volkow, 1992). In a preliminary PET study in four violent pa-
tients (Volkow and Tancredi, 1987), we showed decreased metabolic activity in frontal and left temporal cortex. A more recent PET study done in a group of subjects who had committed or attempted to commit a murder reported abnormalities in prefrontal cortex which the investigators implicated as a predisposing factor for the violent behavior of these subjects (Raine et al., 1994). An association between aggressive behavior and decrements in metabolism in orbitofrontal regions was documented in a PET study done in patients with personality disorders and "aggressive impulse difficulties" (Goyer et al., 1994). G-eneralizability of these frontal abnormalities to other groups of violent patients requires further investigation. The current study investigates regional brain metabolic abnormalities in a group of psychiatric patients with a history of frequent violent behavior. On the basis of our previous results (Volkow and Tancredi, 1987), we hypothesized that repetitive violent offenders would have widespread metabolic derangements and that they would have significantly lower metabolic activity in frontal and temporal cortices than normal comparison subjects. 2. Methods 2.1. Subjects Violent patients. Eight inpatients (mean age : 34 years, SD : 11) from the State Psychiatric Hospital in Harris County (Houston, TX) who fulfilled DSM-III-R diagnostic criteria for intermittent explosive behavior or for antisocial personality disorder (American Psychiatric Association, 1987) were studied. We selected subjects who had a past history of repetitive violent behavior characterized by its purposelessness and for whom their violent behavior had led to legal arrest. Purposelessness was defined when an act was performed without a desire to achieve a specific goal. Most of the violent acts were described by the patients either as impulsive behaviors or as intense aggressive responses. Three of the patients had an additional DSM.III-R diagnosis of schizophrenia (n = 2) or schizoaffective disorder (n = 1). None of the subjects had a past or present history of affective disorder. Though most of the patients used drugs of abuse once or twice a week, they were excluded if they had a past or present history of drug dependence (except for nicotine and caffeine). Patients
N.D. Voikow et al./ Psychiatry Research: Neurounaging 61 (1995) 243-253
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Table 1 Clinical and demographic characteristics of violent patients Subject
Age (years)
Diagnosis
Violent behavior
Medication
i 2 3
51 36 31
lED lED lED, schizophrenia
Physical assault to self and others Homicide, self-mutilation Stabbed parents and girlfriend, self-mutilation
None None Haloperidol, 5 rag, p.o., b.i.d.
4
36
lED
None
5 6
26 26
7
24
lED lED, schizophrenia APD
Frequent fights, attempted homicide, violence exacerbated by alcohol Physical assault, homicidal ideation Physical assault, destructive behavior
8
27
IED,
schizoaffective disorder
Physical assault, homicidal ideation, rape of children Homicide, reports pleasure in killing
None Haloperidol, 5 mg, p.o., b.i.d. None
Thioridazine, 25 mg
Note. IED, intermittent explosive disorder; APD, antisocial personality disorder.
were also excluded if they had a history of neurological illness or head trauma leading to loss of consciousness. Because of the difficulties in managing their violent behavior, three of the patients had to be placed on psychoactive medication before the PET study. Table 1 provides clinical and demographic characteristics of the patients. Except for the three patients who were being treated with neuroleptics, none of the other subjects were receiving medications at the time of study. Normal subjects. Eight right-handed males (mean age = 32 years, SD = 7), all medically healthy and with no past or present history of violent behavior, formed the comparison group. Subjects were excluded if they had a past or present history of psychiatric or neurological disease, or if they were dependent on addictive drugs (except for nicotine and caffeine). Presence or absence of psychiatric illness was assessed with mental state and psychiatric history evaluations performed by one of the investigators (N.D.V., C.G., L.T.). None of the comparison subjects were taking medications at the time of study.
(Mullani et al., 1984). An initial transmission scan was obtained using a ring filled with ~gallium (200 million events were collected) to correct for attenuation. In preparation for the emission scans, subjects had two catheters implanted, one in an antecubital vein for radiotracer injection and another in a radial artery for plasma sampling to quantitate glucose and lSF-deoxyglucose (FDG) concentrations. Emission scans were obtained 35-55 min after injection of 6-8 mCi of FDG. Plasma samples were obtained manually, every 30 s for the first 3 min, every minute for the next 7 min, every 5 min for the next 15 rain, and at 15 min thereafter. During the FDG uptake period as well as during the scan, the subjects remained lying in a supine position in the bed of the PET camera with eyes open, ears unplugged, in a dimly lit room with noise kept to a minimum. No stimulations were used during the study. Subjects were requested to lie still during the FDG uptake and scanning period. An investigator remained by the side of the patients to ensure their compliance and that they did not fall asleep.
2.2. Scans PET scans were obtained using the TOFPET camera (full-width/half-maximum = 1.2 cm)
2.3. Image analysis Regions of interest (ROIs) were drawn directly on the PET image by one of the investigators
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31.1). Volkow et al. / Psychiatry Research: Neuroimaging 61 (1995) 243-253
LF PRE
PRE
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L
PRF~F
~ ,'rilL
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Fig. 1. Template for the location of regions of interest used in the analysis of metabolic images. L, left; R, right; PR, prefrontal; F, frontal; P, parietal; TM, temporal medial; TP, temporal posterior; OC, occipital; BG, basal ganglia; THL, thalamus; CBL, cerebellum.
(N.V.) without knowledge of the subject's diagnosis. A template that identified a total of 47 regions in the central seven sequential planes was used. The template was projected directly onto the metabolic images and was manually fitted into the individual image. A given anatomical region was identified in at least two sequential planes. Fig. 1 shows the location of the regions in the template. The 47 regions were grouped into 16 "composite" cortical, subcortical, and cerebellar regions which represented the weighted average of ROIs from different planes corresponding to the same anatomical structure. In addition, an approximate value for "whole brain" was obtained by averaging the activity in the seven central slices. Because the purpose of this investigation was to assess if there were regional brain defects in violent patients, we normalized the regional metabolic values to the whole brain metabolic activity. Differences between normal subjects and violent patients were tested for this relative measure with unpaired t tests. The significance level for comparisons in brain regions for which it was hypothesized a priori that there would be decrements in metabolism in violent patients was set at P < 0.05. Bonferroni corrections for multiple comparisons were applied to differences in other brain regions. To determine whether there was a lateralized effect in the pattern of regional
abnormalities between the groups, a two-factor analysis of variance (ANOVA) (normal subjects vs. violent patients) with repeated measures for hemisphere (right and left) was performed. To assess whether there was a regional effect, a twofactor ANOVA (normal subjects vs. violent patients) with repeated measures for regions (prefrontal, frontal, parietal, medial temporal, temporal-posterior, and occipital) was performed. To obtain a quantitative estimate of the frequency of regional defects in the brains of violent patients, we obtained the z-transformed values for the regional measures using the regional means and standard deviations (SD) from the normal subjects. The number of regions that were 2 SD outside these z-transformed values was quantified for the normal subjects and the violent patients, and differences between groups were compared by X2 analysis. 3. Results Visual inspection of the images revealed relatively large hypometabolic areas in many of the brains of the violent patients but not in the normal comparison subjects. Figs. 2 and 3 show representative images for a normal subject and a violent individual (subject 7). This patient had decreased metabolic activity throughout various planes in
N.D. Volkow et al. / Psychiatry Research: Neuroimaging 61 (1995) 243-253
247
Fig. 2. Brain glucose metabolic image from a normal subject. Nine sequential planes from the top to the bottom of the brain are shown. The scale to the right represents the relative concentration of lSF-deoxyglucose. Images have been normalized to the highest value for the individual. Left side of the brain is at the right side of the image. Fig. 3. Brain glucose metabolic image from a violent patient. Note the marked relative decrease in glucose metabolism throughout the left hemisphere.
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N.D. Volkow et aL / Psychiatry Research: Neuroimaging 61 (1995) 243-253
1.40
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1.oo
cO ¢yJ (D
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rr 0.80
0.60
RPR LPR
RF
LF
RP
LP RTM LTM RTP LTP FIDC LOC RBG LBG THL CBL
Fig. 4. Average values for relative measures of regional brain metabolism in normal subjects (black) and violent patients (striped). Significant differences between groups: a = e < 0.05; b = P < 0.01. Regions represent: L, left; R, right; PR, prefrontal; F, frontal; P, parietal; TM, temporal medial; TIP, temporal posterior; OC, occipital; BG, basal ganglia; THL, thalamus; CBL, cerebellum.
•~. 1.2 e-
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"~1.05'
Right
Left •
||
•
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:
i-=1.1 "
L_
,- .85
0-
Nml
VIt
Nml
Left
m1.15
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Right
"~ 1.2
VIt
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~, "o
.95 .9
:~ .85
•i
•!
|e
! Nml
Vii
"1 •
Nml
VIt
Fig. 5. Individual values for relative metabolism in fight and left prefrontal and medial temporal cortex for normal subjects (Nml) and violent patients (Vlt),
N.D. Volkow et al./Psychiatry Research: Neuroimaging 61 (1995) 243-233
249
Table 2 Relative metabolic values in normal subjects and violent patients with and without neuroleptic treatment in prefrontal and medial temporal cortex Region
Normal subjects
Right prefrontal Left prefrontal Right medial temporal Left medial temporal
Violent patients
SD
Mean
SD
Mean
SD
1.08 1.09 1.04 1.07
0.04 0.04 0.04 0.04
1.04 1.04 0.97 i .00
0.05 0.06 0.07 0.04
1.02 i .03 0.96 1.02
0.04 0.03 0.03 0.06
Table 3 Number of regions with values 2 standard deviations outside the regional normative data range
Prefrontal Frontal Parietal Medial temporal Posterior temporal Occipital Basal ganglia Thalamus Cerebellum Total
Drug-free (n = 5)
Mean
the left frontal, temporal, and parietal cortical regions. Comparison of relative metabolic values showed that the violent patients had significantly (P < 0.05) lower metabolism for left and right prefrontal regions, left frontal regions, and left and right temporal medial areas than the normal subjects (Fig. 4). Fig. 5 presents the individual values for the left and right prefrontal and medial temporal regions. To determine if the metabolic abnormalities were due to neuroleptic treatment, we separately tabulated the values for the prefrontal and medial temporal cortex for the violent patients with and without neuroleptic treatment along with the values for the normal subjects (Table 2). Pa-
Regions
Neuroleptic-treated (n = 3)
Normal subjects
Violent patients
Left
Right
Left
Right
0 0 0 0 0 1 0
0 I 0 0 0 0 0 0 0 2
4 3 2 6 3 2 3 I 1 38
3 3 ! 4 1 0 I
tients who were receiving neuroleptics were not responsible for the hypofrontality since prefrontal values were not lower in neuroleptic-treated patients than in drug-free patients. Both subgroups had lower values than normal subjects. Although a significant group effect was observed for the prefrontal (F = 7.5; df= 1, 14; P < 0.014) and for the medial temporal cortex (F - 31; df= 1, 14; P < 0.0001), there was no laterality x group interaction effect, indicating that the reductions in metabolism were present in both hemispheres. The analysis for regional effects (prefrontal, frontal, medial temporal, posterior temporal, parietal, and occipital) revealed a significant group x region interaction effect (F = 13; df= 5, 14; P < 0.0001) indicating a greater reduction in metabolism for prefrontal and medial temporal regions. Analysis of the z-transformed regional values revealed that seven of the eight violent patients had cortical areas of decreased relative metabolism in two or more of their brain images. This pattern was seen only for one of the brain images in two normal subjects. Comparison of the number of areas that were abnormal showed the violent patients had significantly (X2 = 35.72, P < 0.0001) more regions that were below 2 SD (38 regions) outside the z-transformed values than did the normal subjects (2 regions). Table 3 shows the location of these regional abnormalities in the normal subjects and in the violent patients. Although the most frequently abnormal regions were located in frontal and temporal areas, there were also abnormalities in parietal, occipital, and subcortical
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regions. Abnormalities occurred more frequently in the left than in the right hemisphere, but this difference was not statistically significant. 4. Discussion
This study documents abnormal regional brain metabolic activity in repetitively violent patients. Similar to our previous study (Volkow and Tancredi, 1987), the most frequently affected brain areas in the violent patients were the prefrontal and the temporal medial cortex. Both prefrontal and medial temporal brain regions have been frequently implicated in the pathogenesis of violent behavior in neurologic and psychiatric patients (Poeck, 1969; Williams, 1969; Lorimer, 1972; Yeudall et al., 1982; Krieger, 1985; Adams and Victor, 1989). As in our previous study (Volkow and Tancredi, 1987), the prefrontal cortex was found to be abnormal in this group of violent patients. Metabolic derangements in prefrontal cortex were similarly observed in individuals who had attempted or had committed a murder (Raine et al., 1994). Abnormalities in frontal metabolism have also been documented in patients with personality disorders with a history of aggressive behaviors (Goyer et al., 1994). The consistency of the findings of frontal hypometabolism in these four studies, each of which investigated subjects with different types of violent behaviors, would suggest that deficits in metabolism of frontal regions may underlie a predisposition for violence. However, decreases in frontal metabolism have also been documented in a wide variety of psychiatric and neurological disorders not associated with violence. It could be argued that frontal hypometabolism is a nonspecific finding common to many forms of cerebral pathology. The frontal cortex is histologically and functionally heterogeneous, and investigation of regions within the frontal cortex that are abnormal may start to reveal some specificity. It is also possible that what characterizes pathology for a given disease is not an abnormality in one brain region but rather the pattern of brain abnormalities. For example, while schizophrenic patients have been shown to have an hypofrontal pattern of metabolic activity, they also have subcortical metabolic
changes. For the present group of violent patients, the hypofrontality occurred in the presence of hypometabolism in medial temporal cortex. One could speculate that because the prefrontal cortex serves to control behavior (Luria, 1966), a lower threshold for the perception of anger secondary to abnormalities in medial temporal areas may be followed by a violent reaction in a subject who lacks an adequate frontal inhibitory control mechanism. Neurochemically, both impulsive and aggressive behaviors have been linked to decreased serotonin activity (Virkunnen et al., 1994a, 1994b). The prefrontal cortex sends efferents to both rostral and caudal raphe nuclei where most of the cells of origin of the serotonin system are located (Heimer, 1994); thus, it could be postulated that dysfunction of prefrontal regions disrupts serotonin activity in the brain. Because the prefrontal cortex is involved in the organization of behavior, abstraction, and consciousness (Luria, 1966), its disruption could also facilitate violent behavior indirectly by interfering with the individual's perception of the situation and with the understanding of ethical concepts as well as by decreasing the repertoire of alternative behaviors. Violent subjects were also found to have significantly lower metabolism in medial temporal regions compared with normal subjects. Due to the limited spatial resolution of the PET instrument used in the study, the medial region selected was relatively large and comprised insula, amygdala, hipoccampus, and uncus. These brain regions are known to play an important role in the regulation and expression of emotions including aggressive behaviors (Goldstein and Huber, 1974; Mirsky and Harman, 1974; Albert and Walsh, 1984). The temporal lobe circuits involved in aggression have testosterone neurons (Stumpf, 1980), and they also receive serotonergic innervation, both of which are postulated to modulate agonistic behavior (Albert and Walsh, 1984; Adams and Victor, 1989). The temporal medial cortex is neuroanatomically connected with other limbic structures, such as the hypothalamus, which have been directly associated with aggressive behaviors (Mark and Swelt, 1974). It is also neuroanatomically connected with cortical association areas and has been postulated to serve as a synap-
N.D. Volkow et al./ Psychiatry Research: Neuroimaging 61 (1995) 243-253
tic buffer between external reality and internal urges (Mesulam, 1985) that, if disrupted, could disturb the flexibility of the individual to respond appropriately to inner needs and environmental situations. Temporal metabolic abnormalities were not detected in the studies done on the subjects who had attempted or committed a murder (Raine et al., 1994). Discrepancies could reflect different experimental conditions; in the study of Raine et al., subjects performed the CPT test and were scanned while medication free, whereas for the current study subjects were scanned with no stimulation and three of them were receiving neuroleptic medication. However, discrepancies could also reflect differences between the subject groups. The study of Raine et al. selected subjects on the basis of a history of attempted or committed murder, whereas in the current study selection was based on a history of frequent violent behavior. Subjects in this investigation were inpatients in a psychiatric hospital; seven had a diagnosis of intermittent explosive disorder, and one of antisocial personality disorder. Thus, one could postulate that the discrepancy between the two studies may reflect the heterogeneity of violence and that findings may not be generalizable to "violent subjects," per se, but rather reflect abnormalities pertaining to a very specific subgroup of violent patients. Violent patients were characterized by a higher incidence of defects in brain areas that have been implicated as substrates for aggressive behavior, but it would be premature to attribute the patients' violent behavior to their brain abnormalities. Abnormalities in frontal and temporal cortical metabolism, it should be remembered, have also been documented in patients with no history of violent behavior (Volkow and Fowler, 1992). It is more likely that the brain abnormalities were a contributing factor that acted in conjunction with the environmental interactions and the past experience of the individual. Future studies comparing differences between violent patents with frontal and temporal abnormalities with patients with the same pattern of abnormalities but without a history of violence may enable investigators to understand better the circumstances under which these abnormalities facilitate violent behaviors.
251
Also, imaging studies on violent patients have been done mostly in subjects who were not violent at the time of the study. Future studies should be designed so that patients are assessed while on a mental state resembing that when they become violent. This could be achieved by using pharmacological challenges with psychoactive drugs that are known to facilitate violent behaviors (e.g., alcohol) and/or using stimulation paradigms that elicit anger (e.g., loud noise). Such activation studies may enable investigators to determine the extent to which particular brain regions are involved in the experience of anger and in the expression of violent behavior. They will also aid in determining whether the involvement of a given brain region is facilitatory or is one of inhibitory control. A limitation of this study was that three of the patients had an additional diagnosis of schizophrenia and were receiving neuroleptic medication at the time of the study. Hence, the abnormalities in these subjects are confounded by the disease process and the use of neuroleptics. Because neuroleptics have sometimes been shown to accentuate hypofrontality in schizophrenic patients, it could be argued that the hypofrontality in the violent patients was due to medication. However, there were no differences in frontal metabolism between neuroleptic-treated violent patients and their unmedicated counterparts, indicating that the hypofrontality was not a medication effect. The mechanisms underlying hypofrontality in this group of violent patients cannot be ascertained but are probably diverse, including head trauma, antipsychotic medication, substance abuse, and mental illness. Because patients were not studied with magnetic resonance imaging, it was not possible to determine the extent to which hypofrontality in these patients was associated with structural brain defects. Though patients were excluded if they had experienced trauma leading to loss of consciousness, it is possible that some patients may have lied about their histories, experienced memory lapses, or suffered from injuries that did not lead to loss of consciousness but nonetheless induced brain damage. The two groups of subjects were not comparable with respect to racial representation (violent group: 3 blacks, 2 Hispanics, and 3 Caucasians; comparison group: 1
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black, 1 Hispanic, and 6 Caucasians), but this difference is unlikely to have contributed to the findings. This study documents decrements in metabolic activity in prefrontal and medial temporal cortex in repetitive violent offenders. The consistency of the finding of frontal metabolic decrements in heterogeneous groups of violent subjects suggests that decreased frontal activity may facilitate, under appropriate circumstances, the emergence of violent or aggressive behaviors. The role that abnormalities in mesial temporal cortex play in the emergence of frequent violent behaviors requires further investigation. The increasing prevalence of violence in our society poses a sense of urgency for understanding the neuroanatomical substrates underlying violent behavior in humans. The search for causal links between violent behaviors and neuroanatomical defects has important scientific, therapeutic, social, and legal implications (Tancredi and Volkow, 1988; Mayberg, 1992); and its complexity should not deter investigation. Future studies evaluating more homogeneous groups of violent patients studied with stimulation paradigms designed to trigger violent or aggressive responses may enable investigators to start to understand the role that specific brain abnormalities play in the emergence of violent behaviors. Acknowledgments This research was supported in part by the U.S. Department of Energy under Contract DE-ACO276CH00016 and National Institutes of Health (AA 09481). The authors thank C. Wong and D. Patel for technical assistance. References Adams, R.D. and Victor, M. (1989) The limbic brain and the neurology of emotion. In: Principles of Neurology. McGraw Hill, New York. Albert, D.J. and Walsh, M.L. (1984) Neural systems and the inhibitory modulation of agonistic behavior: a comparison of mammalian species. Neurosci Biobehav Rev 8, 5-24. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. Brown, G.L., Ballenger, J.C., Minichiello, M.D. and Goodwin, F.K. (1979) Human aggression and its relationship to
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