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Obsessive-compulsive disorder: Is there a frontal lobe dysfunction?
Obsessive-Compulsive Lobe Dysfunction?
Disorder: Is There a Frontal
Sumant Khanna
Obsessive-compulsive
disorder
biochemical
this has revived interest in its biological
markers;
has recently
been found
to be associated
with various
basis. Most qf the work
to date has concentrated
on the neurotransmitters
involved. In this presentation,
from electrophysiologicui,
neuropsychological,
scan, lesion, and psychosurgical
are integrated
evidence studies
to .focus on a possible ~frontal dysfun~ti~F1 in this disorder.
Introduction The evidence for a biological substrate for obsessive-compulsive disorder (OCD) has been gradually mounting (Turner et al. 1985). However, the implications have been more for the neurotransmitter involved-serotonin-thy for the site of the dysfunction (Yarvura Tobias and Bhavagan 1977). Luria (1966) believed in the localization of function to specific areas of the brain, in contrast with the generalists who believe that the whole of the cortex is implicated in all such phenomena. The evidence for localization of the dysfunction in OCD has recently gained support from cerebral glucose metabolic studies (Baxter et al. 1987) and from certain electrophysiological considerations (Khanna et ai. 1987a). In this presentation, an attempt is made to undertake a selective review of the evidence for a frontal lobe dysfunction in OCD.
Electrophysiological
Evidence
The elec~oen~eph~ogram (EEG) has been found to be abnormal in some cases of obsessive-compulsive disorder (Rockwell and Simons 1947; Gibbson and Kennedy 1960; Ingram and McAdam 1960). In most cases, the disturbance noted on visual analysis has been nonspecific. Epstein and Bailine ( 197 1) found temporal lobe spikes and theta waves in the sleep EEG during stage 1 and REM of three subjects with OCD. Bingley and Persson (1978) found increased frontotemporal theta activity in 5 of 35 subjects with OCD. Although most of their cases with abno~~ EEGs had nons~cific theta activity, lnsel et al. (1983) found intermittent left temporal sharp waves in 2 of 18 cases. In their review of OCD subjects who had an EEG done, Jenike and Brotman (1984) found
From the Department of Psychiatry, National fnstitute of Mental Health and Neuroscience, Bangalore, fndia. Address reprint requests to Dr. Sumsn; Khmna. ~pa~ment of Pry&&try, National institute of MrntslHealthand Neuroscmces. Bangafore 560029, India. Recewed October 5, 19X7: revised January 6. 198X.
1 IYXXSooety of Biological
P\ychiatr)
O(X~h-3L2.i~XXl%0~.50
Obsessive-Compulsive Disorder and Frontal Lobe
BIOL PSYCHIATRY 1988;24:602-613
603
disturbances predominandy in the temporal and frontotemporal leads. These clinical studies have shown abnormalities predominantly in the frontal and temporal region. Computerized EEG has been studied in two reports. Flor-Henry et al. (1979) did not study frontal leads, but nevertheless found evidence of a dominant hemisphere dysfunction in OCD. Khanna et al. (1987b) found decreased power in the nondominant frontomedial and posterior temporal regions. There were no significant differences in coherence observed from these sites. Evoked potential studies have focused on baseline studies and on those involving cognitive processing. Changes in some of the early latency evoked potentials (Shagass et al. 1984a,b) have been interpreted differently to implicate increased left hemisphere responsiveness, left frontal dysfunction and increased cortical arousal. Although these changes have not been observed in middle latency potentials (Khanna et al. 1988a), when cognitive processing is involved, there has been an attenuation of the middle components (Cieselki et al. 1981; Beech et al. 1983). The role of the frontal lobes in such cognitive processes is implicit, and such a dysfunction is more likely in OCD. The absence of changes in middle latency potentials without cognitive processing has been also interpreted as an absence of centroparietal and centrotemporal dysfunction in OCD. Habituation is regarded as a function of the subcortical structures, which are essential for attention. No difference was found in the habituation of evoked potentials in OCD as compared with normals (Khanna et al. 1988b). There have been various studies of slow potentials in OCD. Timsit-Berthier et al. (1973) found a more prolonged postimperative negativity in OCD subjects. A higher amplitude of the late component of the contingent negative variation has been repeatedly found (McCallum and Walter 1968; Timsit-Berthier et al. 1973; Sartory and Master 1984; Khanna et al. 1988~). Skinner and Yingling (1976) have stressed the role of the mesencephalic reticular formation, with modulation by the frontal granular cortex, in the genesis of these potentials. There have been two reports about the Bereitschuftspotentiaf in OCD. Cazzullo et al. (1981) could not record this potential from three subjects with OCD. Khanna et al. (1987~) found a significantly decreased onset latency in 44 subjects with OCD. The role of frontal structures, such as the supplementary motor area (Deecke and Komhuber 1978), is stressed in the genesis of this potential. Thus, studies involving the electroencephalogram, with visual and computerized analysis, and with evoked potential and slow potential studies, all tend to implicate some association of frontal region dysfunction with OCD.
Neuropsychological
Studies
Flor-Henry et al. (1979) reported that evidence from the Halstead-Reitan battery and some additional tests implicated frontal dysfunction in 11 subjects with OCD. However, Insel et al. (1983) could not replicate these findings in their 18 subjects. Their values for controls were similar to the values reported for OCD subjects in the earlier study. It must also be kept in mind that this battery cannot differentiate schizophrenics and affective disorder subjects (Klonoff et al. 1970; Donnely et al. 1972) from patients with organic lesions. In a single case report, Khanna et al. (1985) found frontal dysfunction in a subject who developed OCD 3 years after head injury. An attempt was made to compare obsessions with perseveration, and similarities with the premotor syndrome described by Luria (1966) were highlighted.
S. Khanna
604
Studie s with Scans Insel et al. f 1983) found no difference between the ventricular brain ratios on computed tomography (CT) scans of OCD subjects and controls. None of the OCD subjects had a ratio greater than 2 standard deviations above the control mean. However, this ratio did correlate negatively and significantly with the difference between verbal IQ and performance IQ. The latter could not be regarded as an indicator of neurological involvement. and the authors thought this finding was due to the very high verbal IQs in OCD subjects. Asymmetry measures did not differentiate between OCD and control groups. Mild to moderate changes suggestive of cortical atrophy were present in the oldest OCD subject and his matched control. Thus, these authors failed to find any evidence suggestive of structural change in the brains of OCD subjects, the only limitation being the resolution of the CT scan. Behar et al. (1984) studied CT scans in 16 adoI~scent OCD subjects. There was a significant reduction in the ventricular brain ratio in OCD. There was some suggestion that patients who had rituals without associated thoughts were more likely to have enlarged ventricles. No significant correlations were found between ventricular size and any other clinical variable. Baxter et al. ( 1987) studied 14 subjects with OCD by positron emission tomography and the fluorodeoxyglucose method. They found an increase in the left orbital gyrus and bilaterally in the caudate. A similar trend was noted in the right orbital gyms. When comparing the activity of the left orbital gyms with the rest of the ipsilateral hemisphere. the authors found that this was significantly high and remained so even after treatment in IO subjects. The caudate/ipsilateral hemisphere ratio, which was initially comparable with normals, increased significantly in trazodone responders. It is worth noting that a similar trend in depression, albeit from subnormal to normal, had been described earlier in the caudate nucleus by the same authors (Baxter et al. 1985). Thus, an increased bifrontal and bicaudate functional state in OCD is suggested by this study; this became more marked after treatment in the caudate nuclei. Furthermore, total cerebral, caudate, and orbital gyri glucose metabolic rates were lower in unipolar depressives as compared with OCD, but this did not persist when the metabolic rates of the orbital gyri or the caudate nuclei were compared with the rates for the ipsilateral hemisphere. The authors went on to stress the importance of the left orbital gyrus and the caudate nuclei in OCD. They hypothesized that in acutely symptomatic OCD, cerebra1 activity is so high that the caudate nuclei are unable to carry out their integrative functions. The sustained high orbitofrontal/hemisphere ratio is regarded as a manifestation of a vulnerability for OCD, or a trait marker. When the caudate nuclei is unable to integrate cortical inputs, it results in the OCD state. The findings of this study have to be viewed with some caution, as too little is known about positron emission tomography to control all possible variables, including the effect of trazodone on cerebral metabolism. Also, the changes in the caudate nuclei under treatment have shown a similar trend in depression and OCD; perhaps in OCD subjects they reflect the lifting of secondary depression. The literature on the overlap between depression and OCD is abundant (e.g., Jenike 1983) and should not confuse the findings. The authors found that there was no significant correlation between baseline depression and obsessional scores, though there was a significant correlation in the percentage decrease of these scores. This study provides some evidence implicating a hyperfunctional frontal lobe as a probable trait marker for OCD. The involvement of the caudate nuclei could perhaps have been due to depressive symptomatology.
Obsessive-Compulsive Disorder and Frontal Lobe
BIOL PSYCHIATRY 1988:24:602-613
605
Zohar et al. (1988) studied cerebral blood flow by xenon-133 inh~ation before and after relaxation, in vivo exposure, and imaginal flooding in OCD. Total cortical blood flow increased markedly during imaginal flooding, but decreased, even below relaxation levels, during in vitro exposure. These changes were found mostly in the left hemisphere, with greatest increase in the left temporal region. The greatest decrease during in vivo exposure was in the left parietooccipital region. The order effect of behavioral tasks was an uncontrolled variable. This dissociation between cerebral blood flow during in vivo exposure and flooding is difficult to explain. The authors hypothesized that the intense discomfort induced by in vivo exposure is mediated by subcortical structures, with relative inhibition of cortical function. It is thus qualitatively different from imaginal flooding, over which the patient has more control. On the basis of this explanation by the authors, we are faced with the possibihty that in vivo exposure cerebral blood flow may represent a hy~functioning of some part of the brain; the evidence points to the posterior left hemisphere. However, imaginal flooding may result in increased left temporal flow because of the increased activity of the parietotemprooccipital association areas, which are probably involved in the creation of such images. Thus, although there is no strong evidence for structural lesions in OCD, recent evidence suggests frontal hypermetabolism in this disorder. Childhood OCD however may be a separate subgroup.
Lesion Studies Minski (1933) reported a case of OCD in a patient with a left frontal tumor. On the basis of electrical stimulation and lesion studies, Grey-Walter (1966) concluded that overactivity of the frontotem~~ system was related to affective dis~rbances; whereas overactivity of the cingulate system led to obsessive-compuIsive phenomena. Talairach et al. (1973) reported stereotyped repetitive movements on anterior cingulate gyrus stimulation in 52 drug-resistant epileptics. Brickner (1940) reported compulsive repetition of the alphabet on stimulation of area 6 in a patient with OCD. However, when this area was excised, it did not reveal any pathology. Pallidostriatal necrosis was found in a subject who developed OCD after an encephalitis that was presumably related to a wasp sting (Laplane et al. 1981). Pitman (1982) provided an animal model for OCD in the form of a hippocampectomized rat. Similar effects were reported by Morris et al. (1982). Paunovic (1984) reported a patient who developed OCD after anterior dominant cerebral infarction. Khanna et al. (1985) reported a case in which OCD developed after head injury and reviewed ~st~aumatic OCD. In this case, at the time of development of the obsessional syndrome, the patient had p~dominant neuropsychological deficits in the frontal regions. The authors sought to compare the phenomena of obsession and of perseveration encountered in this case: in the former condition, there was a total inability to change set, in the other, it was difficult to do so. This particular patient showed good response to Damphetamine (Khanna and Janakiramaiah 1984). Luria (1969) considered that the premotor syndrome was characterized by (1) deautomatization of complex motor acts and (2) revival of primary automatisms. There is a defect in successive kinetic organization that results in compulsive automatisms if the basal ganglia become involved. Disturbances in speech and dynamic thinking are also reported with lesions of the inferior part of the dominant hemisphere premotor area. The disturbances described are more marked when the tumors are deep seated. The prefrontal syndromes are characterized by disturbances of complex forms of active purposive behavior and an impaired critical attitude toward the patient’s own defects. Luria (1969)
606
BlOtPSYCHIATRY 1988:24%02-hi?
Table 1. Psychosurgery
S. Khanna
in OCD
Operation
Reference
n
++
+
Oi
Board of Control (1947) Freeman and Watts (1950) Hohman et al. (1951) Moore (1952)
29 121 8 I
59 57 100 71
31 28 0 0
IO
29
Transorbital leukotomy
Freeman and Watts (1950)
34
65
24
II
Bimedial leukotomy
Bernstein et al. (1975)
27
81
4
IS
Orbital leukotomy
Knight and Tredgold (1955) Sykes and Tredgoid (1964)
II 24
18 29
55 46
27 25
Rostra1 feukotomy
Pippard i 1955)
26
46
15
39
Sterotaxic tractotomy
Strom-Olsen and Carlisle (1971) Coktepe et al. (1975) Bridges et al. f 1973)
20 18 24
SO 50 67
15 33 25
30 17 8
Cingulectomy
Whitty et al. (1952) Brown and Lighthill (1968) Paillas et al. (1971) Gaches et al. (1972) Meyer et al. (1973) Bailey et al. (1977)
4 31 20 20 3 36
7s x7 45 80 67 83
25 7 30 10 33 14
0 6 2s IO 0 3
Thalamotomy
Spiegel (1953)
3
0
33
67
Limbic Ieukotomy
Mitchell Heggs et al. (1976)
27
66
22
12
Capsulotomy
Lopez Ibor and Lopez-Ibor Alino (1977) Bingley et al. (1977) Fodstad et al. (1982)
57 35 2
74 71 loo
17 29 0
9 0 0
Prefrontal leukotomy
If 0
further states that in lesions of this area, the movements cease to be controlled by the program assigned and fall under the influence of irrelevant factors. There is also a dysregulation of voluntary actions. Destructive lesions of the orbital cortex result in a disinhibition characterized by facetiousness, sexuai and personal hedonism, irritability, and a lack of socially appropriate concern for others (Stuss and Benson 1986). Such syndromes are the behavioral opposites of the symptoms and typical personality manifestations seen in individuals with OCD (Baxter et al. 1987). Studies involving stimulation of the frontal lobe and lesions in these areas result in phenomena similar to obsessions and compulsions. This evidence makes it difficult to implicate a specific part of the frontal lobe, and it is likely that various parts are involved in the necessary circuits.
Psychosurgical
Evidence
O’Callaghan and Can-011(1982) reviewed the literature on existing studies and found that OCD was the second best responder to psychosurgery. A list of procedures used and outcome rates is given in Table 1. In general, lesions of the cingufate gyrus and lower medial quadrant of the frontal lobe have been found useful. For OCD, the following
Obsessive-CompulsiveDisorder and Frontal Lobe
BIOL PSYCHIATRY 1988;24:402-613
607
procedures were found useful in at least half of the subjects: prefrontal leukotomy, transorbital leukotomy, limbic sectioning, bimedial frontal leukotomy, cingulectomy, and capsuiectomy. In most cases, there is no actual elimination of the instrusive thought; what happens is that the thought becomes less intrusive and anxiety provoking, it is resisted less, and causes less interference (Kalinowsky 19’73). Latinen and Vilkki (1973) have found that anterior septal ventral stereotactic cingulotomies below and in front of the knee of the corpus callosum were effective for tension, but totally ineffective in OCD. Thus, the critical site seems to be around area 24 of Brodman or the dorsal part of the anterior cingulate gyrus. Hassler and Dieckmann (1967, 1970) performed unilateral and bilateral stereotactic thalamotomies in patients with obsessions and compulsions. Coagulation of the medial thalamic nuclei led to relief from obsessions, whereas the rostra1 intralaminar thalamic nuclei was similarly implicated for compulsions. Hassler (1980) reported that right-sided disruption of thalamofrontal pathways was in some cases sufficient to produce clinical recovery. Some patients required subsequent operations on the dominant hemisphere. Bridges and Goktepe (1973) identified age of onset after 30, presence of depression, acute onset, and onset related to pregnancy as being good prognostic factors for psychosurgery in OCD. More important is the issue as to where the critical lesion is in these various psychosurgery procedures. Flor-Henry (1975) has stressed the role of the anterior cingulum. Knight (1973) reported recovery in three subjects with cingulectomy where subcaudate ~actotomy had not worked. In general, most procedures that result in isolation of the frontal cortex have been useful in OCD (Bridges et al. 1973), with only one study using unilateral lesions (Hassler 1980). The remarkable success of psychosurgical sectioning of frontal pathways in OCD is a very strong indication of frontal lobe involvement and modulation in OCD and provides unequivocal evidence that the frontal lobe is part of a dysfunctional circuit in this disorder.
Animal Models MacLean (1985) addresses limbic structures in an evolutional perspective. Although the amygdala is mainly involved with self-preservation, the septal division was regarded as being more important for feeling and expressive states conducive to sociability and the procreation of species. However, his major stress is on the ~alam~ingulate system, which is unique to humans and absent in reptiles. In addition to various basic behaviors, he refers to six intraoperative behaviors of which two seem relevant here. One is routinizing behavior that links together everything around the clock. Psychotics have repetitions of disrupting subroutines that are probably of striatal origin. In repetitious behavior, he makes a specific reference to acts repeated again and again in connection with some charged situation or train of events, and MacLean (1985) refers to obsessive-compulsive hand washing in this spectrum. However, he does not discuss any specific neuroanatomical substrate for this. However, if one considers it in an evolutionary perspective, then the striatal and thalamocingulate divisions of the limbic system would be of importance. Many authors have argued for OCD being closer to psychosis @or-Henry 1973) in a late~lization model of ~ychopa~ology. Elsewhere, a case for complex motor programming deficits in OCD has been presented (Cummings and Frankel 1985) and experimentally supported (Khanna et al. 1987~). Thus, excessive repetition of such subroutines could be regarded as the basis for OCD, but animal studies have not helped in delineating exactly where this dysfunction lies. Pitman (1982) stressed the importance of the hippocampus in the genesis of OCD.
60X
UIOL PSYCHIATR? 1988:14:802-61.3
S. Khanna
Devenport et al. (198 1) reported persistance, hy~~es~nsivity, stereotypy, rituahsticlike behavior, and reduced spontaneous plasticity in the hipp~am~ctomi~d rat, all of which Pitman regarded as being very similar to compulsions. Similar effects on the rat have been found by Morris et al. (1982). However, the studies of Baxter et al. (1987) did not report any changes in this region in humans. The roIe of animal models in OCD research is questionable. The experience of obsessions is very subjective and even motor compulsions without evidence of intrusive and irrational thoughts cannot be accepted in toto as QCD models. However, MacLean’s ( 1985) model seems to agree at least in part, with psychosurgical evidence, and thus, his theoretical arguments seem to be borne out by human evidence.
Impfir Hassler and Dieckman (1973) proposed that for a thought, the specific complex mechanism is not in itself sufficient. They stressed the impartance of specific and nonspecific pathways the latter involving vigilance, directed attention, and adversion. They believed that the lower neuronal substrate for such activation was the reticular activating system whereas a higher neuronal system-the ~ncothalami~ tract-regoIated the activity of the various cortical circuits for the senses, motility, and integrative functions. In their model for OCD, disinhibition and dominance of the mediothalamic prefrontal pathways comprised the neurophysiological substrate for the “hypertrophy of conscience” in OCD. They further hypothesized that inactivation of the rostra1 intralaminar thalamic nuclei and medial thaiamic nuclei would result in relief of computsions and obsessions, respectively. Baxter et al. f 1987) have argued forcefully for the role of the caudate nuclei in OCD. Impairment of the basal ganglia has been reported to produce perseverative phenomena (Mettler 1955). The importance of the gating function of the basal ganglia in information processing has been stressed (Schneider 1984). and it is thought that when they become dysfunctional. inapprop~ate behaviorai responses can occur. The association with von Economo’s ~ncephaIitis and obsessive-compulsive symptoms tended to correlate with parkinsonian symptoms and suggested basal ganglia involvement (Bender 1935; Schilder 1938; Brickner 1940). Basal ganglia damage has also been noted in a case with OCD (Pulst et al. 1983). Isolated case reports have pointed to a lesion in the globus pallidus (Laplane et al. 1981; Ah-Cherif et al. 19843 Crey-Walter ( 1979) hypothesized that overstimulation of the cinguium led to compulsive behavior. According to Flor-Henry fI973), the obsessional syndrome was anatomically dependent on the central midline structure of the limbic system, namely, the anterior thalamic cingulate gyrus. However, he subsequently modified this view to regard OCD as a dominant frontal dysfunction (Flor-Henry et al. 1979) that was probably secondary to abno~alities in the cingulate gyrus. When there was perturbation of the dominant tem~rallimbi~ system, it resulted in a schizophrenic syndrome, whereas a manic-depressive psychosis was thought to supervene when the disorganization followed a dominant frontal-nondominant frontotemporal gradient. He also found that anterior cingulate lesions were the most effective in relieving OCD (Flor-Henry 1975). Stimulation of the cingulum has been found to result in perseverations (Meyer et al, 1973) and “obsessive” urges (Talairach et al. 1973). The phenomenon of active avoidance has been associated with the ~ingulum (1Marks f987), and this could be generalized to correlate with the resistance experienced in obsessive-compulsive phenomenon.
BIOL PSYCHL4TRY 1988;24:602-613
Obsessive-Compulsive Disorder and Frontal Lobe
609
These studies have implicated the cingulum and the basal ganglia in OCD. Cause and effect, however, are not clear, and the linkage needs to be elucidated further.
An Integration The
studies cited in this review provide tentative evidence for the involvement of the frontal lobe in OCD. Baxter et al. (1987) found higher cerebral metabolic rates in the dominant orbital gyrus, whereas Khanna et al. (1987b) reported hypofunctioning of the nondominant frontomedial region in their work on computerized electroencephalography. These two findings may appear to be contradictory but are not actually so. Serafitinides (1984) suggested in a proposed schema for cerebral lateralization of psychopathology that ruminative and verbal phenomena were more likely to occur in nondominant hemisphere dysfunction due to compensatory or release mechanisms for the rest of the brain. The issue can basically be reconciled in terms of right-left ratios; the findings of Baxter et al. (1987) and Khanna et al. (1987b) both show a change in this ratio toward dominant hemisphere functioning. Thus, it seems possible to conclude that existing evidence on the dysfunction in OCD involves the frontal lobe, with a shift in laterality to the left side. The efficacy of unilateral right-sided thalamofrontal sectioning in OCD (Hassler 1980) thus needs replication. An exact anatomical localization of this dysfunction is difficult to detail at this point in time. The similarity of the premotor and prefrontal syndromes to obsessive-compulsive phenomena and to problems in complex motor programming (Luria 1969) are striking and have already been mentioned. Similarly, lesions of the orbital gyrus result in symptoms opposite to those observed In OCD. It would be difficult to state that the dysfunction in OCD does not exist in any other part of the brain. Various pathways impinge on the frontal lobes, and their function, perforce, is dependent on this input. However, just as Muller (1985) argues for a prefrontal involvement to explain functional psychosis, the evidence reviewed here supports a frontal lobe involvement in OCD. The prefrontal cortex receives inputs from various regions, notably the cingulum, which in turn is connected to the basal ganglia. A primary dysfunction at any of these sites could easily lead to secondary dysfunctions that may mimic the (hypothesized) primary site for obsessive-compulsive symptomatology. The involvement of the cingulum in the Papez circuit for emotions may help explain the commonly observed coexistence of depression. The cause and effect relationship is difficult to differentiate. Further attempts will have to focus on patients before and after behavioral therapy (to avoid drug effects); perhaps, normals can be induced to think repetitively or to have “normal” obsessions (Rachman and deSilva 1978). Neuroanatomical correlates of an increase in obsessions by procedures like in vitro exposure (Zohar et al. 1988) or mCPP administration (Zohar and Insel 1987) are additional strategies that can be used. The current evidence provides tantalizing support for involvement of the frontal lobe in OCD, but does not answer questions about the involvement of other sites or allow us to separate cause and effect.
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obsessional
illness and obsessional
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15.
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N (1984): o-Amphetamine
in obsessive
compulsive
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Phurm-
obsessive compulsive
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SM (1987b): Computerised
electroencephalogram
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Presented at International April 1987.
Khanna S, Mukundan CR, Channabasavanna problem of complex motor programming?
Conference
on New Directions
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par
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dans le
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Pulst SM, Walshe TM, Romero JA (1983): Carbon monoxide poisoning with features of Gilles de la Tourette syndrome. Arch Neural 10443-444. Rachman SJ, deSilva P (1978): Abnormal and normal obsessions. Beh Res Ther 16:223-248. Rockwell FV, Simons DJ (1947): The elec~~nceph~ogmm and persona&y org~isation in the obsessive compulsive reaction. Arck Neural P~chiaf~ 57:71-83. Sartory G, Master D (1984): Contingent negative variation in obsessional patients. Biol Psychiatry 18:253-267.
Schilder P (1938): The organic background of obsessions and compulsions. Am J Psychiatry 94: 1397-1414. Schneider JS (1984): Basal ganglia role in behaviours: Importance of sensory gating and its relevance to psychiatry. Biol Psychiatry 19:1693-1701. Serafitinides EA (1984): EEG lateral asymmetrices in psychiatric disorders. Biol Psycho1 19:237246.
Shagass C, Roemer A, Straumanis JJ, Josiassen RC (1984a): Evoked potentials in obsessive compulsive disorder. Adv Biol Psychiatry 15:69-75. Shagass C, Roemer A, S~aumanis JJ, Josiassen RC (1984b): Distinctive somatosenso~ evoked potential features in obsessive compulsive disorder. Biol P~chia?~ 19:1507-1524. Skinner JE, Yingling CD (1976): Regulation of slow potential shifts in nucleus reticularis thalami by the mesencephalic reticular formation and the frontal granular cortex. Electroencephalogr Clin Neurophysiol40:288-296.
Spiegel EA, Wycis HT, Freed H, Orchinik C (1953): Thalamotomy and hypothalamotomy for the treatment of psychosis. Res Pubi Assoc Nerv Ment Dis 3 1:379-39 1. Strom-Olsen R, Carlisle S (1971): Bifrontal stereotactic tractomy. Br J Psychiatry 118:141-154. Stuss DT, Benson DF (1986): The Frontal Lobes. New York: Raven Press. Sykes MK, Tredgold RF (1964): Restricted orbital undercutting. Br J Psychiatry 110:609-640. Talairach J, Bancaud J, Geier S (1973): The cingulate gyms and human behaviour. Electroencephalogr Clin Neurophysiol34:45-52.
Timsit-Be~hier M, Delanoy J, Konnickx N, Rousseau J (1973): Slow potential changes in psychiatry. Electroencephalogr Clin Neurophysiol 28:4147. Turner SM, Beidel DC, Nathan RGS (1985): Biological factors in obsessive compulsive disorder. Psycho1 Bull 973430-450.
Whitty CWM, Duffield JE, Tow PM, Cairns H (1952): Anterior cingulectomy in the treatment of mental disease. Lancet 1:465-481. Yoga-Tobias
JA, Bhagavan H (1977): L-~ptoph~
in obsessive compulsive disorder. Am J
Psychiatry 134:1298-1299.
Zohar J, Insel TR (1987): Obsessive compulsive disorder: Psychobiological approaches to diagnosis, treatment and pathophysiology. Biol Psychiatry 22:667-687. Zohar J, Insel TR, Foa EB, Steketee G, Berman KF, Weinberger DR, Kozak M, Cohen RM (1988): Physiological and psychological changes during in vivo exposure and imaginal flooding of obsessive compulsive disorder patients. Proceedings of World Congress of Biological Psychiatry (in press).
Disorder: Is There a Frontal
Sumant Khanna
Obsessive-compulsive
disorder
biochemical
this has revived interest in its biological
markers;
has recently
been found
to be associated
with various
basis. Most qf the work
to date has concentrated
on the neurotransmitters
involved. In this presentation,
from electrophysiologicui,
neuropsychological,
scan, lesion, and psychosurgical
are integrated
evidence studies
to .focus on a possible ~frontal dysfun~ti~F1 in this disorder.
Introduction The evidence for a biological substrate for obsessive-compulsive disorder (OCD) has been gradually mounting (Turner et al. 1985). However, the implications have been more for the neurotransmitter involved-serotonin-thy for the site of the dysfunction (Yarvura Tobias and Bhavagan 1977). Luria (1966) believed in the localization of function to specific areas of the brain, in contrast with the generalists who believe that the whole of the cortex is implicated in all such phenomena. The evidence for localization of the dysfunction in OCD has recently gained support from cerebral glucose metabolic studies (Baxter et al. 1987) and from certain electrophysiological considerations (Khanna et ai. 1987a). In this presentation, an attempt is made to undertake a selective review of the evidence for a frontal lobe dysfunction in OCD.
Electrophysiological
Evidence
The elec~oen~eph~ogram (EEG) has been found to be abnormal in some cases of obsessive-compulsive disorder (Rockwell and Simons 1947; Gibbson and Kennedy 1960; Ingram and McAdam 1960). In most cases, the disturbance noted on visual analysis has been nonspecific. Epstein and Bailine ( 197 1) found temporal lobe spikes and theta waves in the sleep EEG during stage 1 and REM of three subjects with OCD. Bingley and Persson (1978) found increased frontotemporal theta activity in 5 of 35 subjects with OCD. Although most of their cases with abno~~ EEGs had nons~cific theta activity, lnsel et al. (1983) found intermittent left temporal sharp waves in 2 of 18 cases. In their review of OCD subjects who had an EEG done, Jenike and Brotman (1984) found
From the Department of Psychiatry, National fnstitute of Mental Health and Neuroscience, Bangalore, fndia. Address reprint requests to Dr. Sumsn; Khmna. ~pa~ment of Pry&&try, National institute of MrntslHealthand Neuroscmces. Bangafore 560029, India. Recewed October 5, 19X7: revised January 6. 198X.
1 IYXXSooety of Biological
P\ychiatr)
O(X~h-3L2.i~XXl%0~.50
Obsessive-Compulsive Disorder and Frontal Lobe
BIOL PSYCHIATRY 1988;24:602-613
603
disturbances predominandy in the temporal and frontotemporal leads. These clinical studies have shown abnormalities predominantly in the frontal and temporal region. Computerized EEG has been studied in two reports. Flor-Henry et al. (1979) did not study frontal leads, but nevertheless found evidence of a dominant hemisphere dysfunction in OCD. Khanna et al. (1987b) found decreased power in the nondominant frontomedial and posterior temporal regions. There were no significant differences in coherence observed from these sites. Evoked potential studies have focused on baseline studies and on those involving cognitive processing. Changes in some of the early latency evoked potentials (Shagass et al. 1984a,b) have been interpreted differently to implicate increased left hemisphere responsiveness, left frontal dysfunction and increased cortical arousal. Although these changes have not been observed in middle latency potentials (Khanna et al. 1988a), when cognitive processing is involved, there has been an attenuation of the middle components (Cieselki et al. 1981; Beech et al. 1983). The role of the frontal lobes in such cognitive processes is implicit, and such a dysfunction is more likely in OCD. The absence of changes in middle latency potentials without cognitive processing has been also interpreted as an absence of centroparietal and centrotemporal dysfunction in OCD. Habituation is regarded as a function of the subcortical structures, which are essential for attention. No difference was found in the habituation of evoked potentials in OCD as compared with normals (Khanna et al. 1988b). There have been various studies of slow potentials in OCD. Timsit-Berthier et al. (1973) found a more prolonged postimperative negativity in OCD subjects. A higher amplitude of the late component of the contingent negative variation has been repeatedly found (McCallum and Walter 1968; Timsit-Berthier et al. 1973; Sartory and Master 1984; Khanna et al. 1988~). Skinner and Yingling (1976) have stressed the role of the mesencephalic reticular formation, with modulation by the frontal granular cortex, in the genesis of these potentials. There have been two reports about the Bereitschuftspotentiaf in OCD. Cazzullo et al. (1981) could not record this potential from three subjects with OCD. Khanna et al. (1987~) found a significantly decreased onset latency in 44 subjects with OCD. The role of frontal structures, such as the supplementary motor area (Deecke and Komhuber 1978), is stressed in the genesis of this potential. Thus, studies involving the electroencephalogram, with visual and computerized analysis, and with evoked potential and slow potential studies, all tend to implicate some association of frontal region dysfunction with OCD.
Neuropsychological
Studies
Flor-Henry et al. (1979) reported that evidence from the Halstead-Reitan battery and some additional tests implicated frontal dysfunction in 11 subjects with OCD. However, Insel et al. (1983) could not replicate these findings in their 18 subjects. Their values for controls were similar to the values reported for OCD subjects in the earlier study. It must also be kept in mind that this battery cannot differentiate schizophrenics and affective disorder subjects (Klonoff et al. 1970; Donnely et al. 1972) from patients with organic lesions. In a single case report, Khanna et al. (1985) found frontal dysfunction in a subject who developed OCD 3 years after head injury. An attempt was made to compare obsessions with perseveration, and similarities with the premotor syndrome described by Luria (1966) were highlighted.
S. Khanna
604
Studie s with Scans Insel et al. f 1983) found no difference between the ventricular brain ratios on computed tomography (CT) scans of OCD subjects and controls. None of the OCD subjects had a ratio greater than 2 standard deviations above the control mean. However, this ratio did correlate negatively and significantly with the difference between verbal IQ and performance IQ. The latter could not be regarded as an indicator of neurological involvement. and the authors thought this finding was due to the very high verbal IQs in OCD subjects. Asymmetry measures did not differentiate between OCD and control groups. Mild to moderate changes suggestive of cortical atrophy were present in the oldest OCD subject and his matched control. Thus, these authors failed to find any evidence suggestive of structural change in the brains of OCD subjects, the only limitation being the resolution of the CT scan. Behar et al. (1984) studied CT scans in 16 adoI~scent OCD subjects. There was a significant reduction in the ventricular brain ratio in OCD. There was some suggestion that patients who had rituals without associated thoughts were more likely to have enlarged ventricles. No significant correlations were found between ventricular size and any other clinical variable. Baxter et al. ( 1987) studied 14 subjects with OCD by positron emission tomography and the fluorodeoxyglucose method. They found an increase in the left orbital gyrus and bilaterally in the caudate. A similar trend was noted in the right orbital gyms. When comparing the activity of the left orbital gyms with the rest of the ipsilateral hemisphere. the authors found that this was significantly high and remained so even after treatment in IO subjects. The caudate/ipsilateral hemisphere ratio, which was initially comparable with normals, increased significantly in trazodone responders. It is worth noting that a similar trend in depression, albeit from subnormal to normal, had been described earlier in the caudate nucleus by the same authors (Baxter et al. 1985). Thus, an increased bifrontal and bicaudate functional state in OCD is suggested by this study; this became more marked after treatment in the caudate nuclei. Furthermore, total cerebral, caudate, and orbital gyri glucose metabolic rates were lower in unipolar depressives as compared with OCD, but this did not persist when the metabolic rates of the orbital gyri or the caudate nuclei were compared with the rates for the ipsilateral hemisphere. The authors went on to stress the importance of the left orbital gyrus and the caudate nuclei in OCD. They hypothesized that in acutely symptomatic OCD, cerebra1 activity is so high that the caudate nuclei are unable to carry out their integrative functions. The sustained high orbitofrontal/hemisphere ratio is regarded as a manifestation of a vulnerability for OCD, or a trait marker. When the caudate nuclei is unable to integrate cortical inputs, it results in the OCD state. The findings of this study have to be viewed with some caution, as too little is known about positron emission tomography to control all possible variables, including the effect of trazodone on cerebral metabolism. Also, the changes in the caudate nuclei under treatment have shown a similar trend in depression and OCD; perhaps in OCD subjects they reflect the lifting of secondary depression. The literature on the overlap between depression and OCD is abundant (e.g., Jenike 1983) and should not confuse the findings. The authors found that there was no significant correlation between baseline depression and obsessional scores, though there was a significant correlation in the percentage decrease of these scores. This study provides some evidence implicating a hyperfunctional frontal lobe as a probable trait marker for OCD. The involvement of the caudate nuclei could perhaps have been due to depressive symptomatology.
Obsessive-Compulsive Disorder and Frontal Lobe
BIOL PSYCHIATRY 1988:24:602-613
605
Zohar et al. (1988) studied cerebral blood flow by xenon-133 inh~ation before and after relaxation, in vivo exposure, and imaginal flooding in OCD. Total cortical blood flow increased markedly during imaginal flooding, but decreased, even below relaxation levels, during in vitro exposure. These changes were found mostly in the left hemisphere, with greatest increase in the left temporal region. The greatest decrease during in vivo exposure was in the left parietooccipital region. The order effect of behavioral tasks was an uncontrolled variable. This dissociation between cerebral blood flow during in vivo exposure and flooding is difficult to explain. The authors hypothesized that the intense discomfort induced by in vivo exposure is mediated by subcortical structures, with relative inhibition of cortical function. It is thus qualitatively different from imaginal flooding, over which the patient has more control. On the basis of this explanation by the authors, we are faced with the possibihty that in vivo exposure cerebral blood flow may represent a hy~functioning of some part of the brain; the evidence points to the posterior left hemisphere. However, imaginal flooding may result in increased left temporal flow because of the increased activity of the parietotemprooccipital association areas, which are probably involved in the creation of such images. Thus, although there is no strong evidence for structural lesions in OCD, recent evidence suggests frontal hypermetabolism in this disorder. Childhood OCD however may be a separate subgroup.
Lesion Studies Minski (1933) reported a case of OCD in a patient with a left frontal tumor. On the basis of electrical stimulation and lesion studies, Grey-Walter (1966) concluded that overactivity of the frontotem~~ system was related to affective dis~rbances; whereas overactivity of the cingulate system led to obsessive-compuIsive phenomena. Talairach et al. (1973) reported stereotyped repetitive movements on anterior cingulate gyrus stimulation in 52 drug-resistant epileptics. Brickner (1940) reported compulsive repetition of the alphabet on stimulation of area 6 in a patient with OCD. However, when this area was excised, it did not reveal any pathology. Pallidostriatal necrosis was found in a subject who developed OCD after an encephalitis that was presumably related to a wasp sting (Laplane et al. 1981). Pitman (1982) provided an animal model for OCD in the form of a hippocampectomized rat. Similar effects were reported by Morris et al. (1982). Paunovic (1984) reported a patient who developed OCD after anterior dominant cerebral infarction. Khanna et al. (1985) reported a case in which OCD developed after head injury and reviewed ~st~aumatic OCD. In this case, at the time of development of the obsessional syndrome, the patient had p~dominant neuropsychological deficits in the frontal regions. The authors sought to compare the phenomena of obsession and of perseveration encountered in this case: in the former condition, there was a total inability to change set, in the other, it was difficult to do so. This particular patient showed good response to Damphetamine (Khanna and Janakiramaiah 1984). Luria (1969) considered that the premotor syndrome was characterized by (1) deautomatization of complex motor acts and (2) revival of primary automatisms. There is a defect in successive kinetic organization that results in compulsive automatisms if the basal ganglia become involved. Disturbances in speech and dynamic thinking are also reported with lesions of the inferior part of the dominant hemisphere premotor area. The disturbances described are more marked when the tumors are deep seated. The prefrontal syndromes are characterized by disturbances of complex forms of active purposive behavior and an impaired critical attitude toward the patient’s own defects. Luria (1969)
606
BlOtPSYCHIATRY 1988:24%02-hi?
Table 1. Psychosurgery
S. Khanna
in OCD
Operation
Reference
n
++
+
Oi
Board of Control (1947) Freeman and Watts (1950) Hohman et al. (1951) Moore (1952)
29 121 8 I
59 57 100 71
31 28 0 0
IO
29
Transorbital leukotomy
Freeman and Watts (1950)
34
65
24
II
Bimedial leukotomy
Bernstein et al. (1975)
27
81
4
IS
Orbital leukotomy
Knight and Tredgold (1955) Sykes and Tredgoid (1964)
II 24
18 29
55 46
27 25
Rostra1 feukotomy
Pippard i 1955)
26
46
15
39
Sterotaxic tractotomy
Strom-Olsen and Carlisle (1971) Coktepe et al. (1975) Bridges et al. f 1973)
20 18 24
SO 50 67
15 33 25
30 17 8
Cingulectomy
Whitty et al. (1952) Brown and Lighthill (1968) Paillas et al. (1971) Gaches et al. (1972) Meyer et al. (1973) Bailey et al. (1977)
4 31 20 20 3 36
7s x7 45 80 67 83
25 7 30 10 33 14
0 6 2s IO 0 3
Thalamotomy
Spiegel (1953)
3
0
33
67
Limbic Ieukotomy
Mitchell Heggs et al. (1976)
27
66
22
12
Capsulotomy
Lopez Ibor and Lopez-Ibor Alino (1977) Bingley et al. (1977) Fodstad et al. (1982)
57 35 2
74 71 loo
17 29 0
9 0 0
Prefrontal leukotomy
If 0
further states that in lesions of this area, the movements cease to be controlled by the program assigned and fall under the influence of irrelevant factors. There is also a dysregulation of voluntary actions. Destructive lesions of the orbital cortex result in a disinhibition characterized by facetiousness, sexuai and personal hedonism, irritability, and a lack of socially appropriate concern for others (Stuss and Benson 1986). Such syndromes are the behavioral opposites of the symptoms and typical personality manifestations seen in individuals with OCD (Baxter et al. 1987). Studies involving stimulation of the frontal lobe and lesions in these areas result in phenomena similar to obsessions and compulsions. This evidence makes it difficult to implicate a specific part of the frontal lobe, and it is likely that various parts are involved in the necessary circuits.
Psychosurgical
Evidence
O’Callaghan and Can-011(1982) reviewed the literature on existing studies and found that OCD was the second best responder to psychosurgery. A list of procedures used and outcome rates is given in Table 1. In general, lesions of the cingufate gyrus and lower medial quadrant of the frontal lobe have been found useful. For OCD, the following
Obsessive-CompulsiveDisorder and Frontal Lobe
BIOL PSYCHIATRY 1988;24:402-613
607
procedures were found useful in at least half of the subjects: prefrontal leukotomy, transorbital leukotomy, limbic sectioning, bimedial frontal leukotomy, cingulectomy, and capsuiectomy. In most cases, there is no actual elimination of the instrusive thought; what happens is that the thought becomes less intrusive and anxiety provoking, it is resisted less, and causes less interference (Kalinowsky 19’73). Latinen and Vilkki (1973) have found that anterior septal ventral stereotactic cingulotomies below and in front of the knee of the corpus callosum were effective for tension, but totally ineffective in OCD. Thus, the critical site seems to be around area 24 of Brodman or the dorsal part of the anterior cingulate gyrus. Hassler and Dieckmann (1967, 1970) performed unilateral and bilateral stereotactic thalamotomies in patients with obsessions and compulsions. Coagulation of the medial thalamic nuclei led to relief from obsessions, whereas the rostra1 intralaminar thalamic nuclei was similarly implicated for compulsions. Hassler (1980) reported that right-sided disruption of thalamofrontal pathways was in some cases sufficient to produce clinical recovery. Some patients required subsequent operations on the dominant hemisphere. Bridges and Goktepe (1973) identified age of onset after 30, presence of depression, acute onset, and onset related to pregnancy as being good prognostic factors for psychosurgery in OCD. More important is the issue as to where the critical lesion is in these various psychosurgery procedures. Flor-Henry (1975) has stressed the role of the anterior cingulum. Knight (1973) reported recovery in three subjects with cingulectomy where subcaudate ~actotomy had not worked. In general, most procedures that result in isolation of the frontal cortex have been useful in OCD (Bridges et al. 1973), with only one study using unilateral lesions (Hassler 1980). The remarkable success of psychosurgical sectioning of frontal pathways in OCD is a very strong indication of frontal lobe involvement and modulation in OCD and provides unequivocal evidence that the frontal lobe is part of a dysfunctional circuit in this disorder.
Animal Models MacLean (1985) addresses limbic structures in an evolutional perspective. Although the amygdala is mainly involved with self-preservation, the septal division was regarded as being more important for feeling and expressive states conducive to sociability and the procreation of species. However, his major stress is on the ~alam~ingulate system, which is unique to humans and absent in reptiles. In addition to various basic behaviors, he refers to six intraoperative behaviors of which two seem relevant here. One is routinizing behavior that links together everything around the clock. Psychotics have repetitions of disrupting subroutines that are probably of striatal origin. In repetitious behavior, he makes a specific reference to acts repeated again and again in connection with some charged situation or train of events, and MacLean (1985) refers to obsessive-compulsive hand washing in this spectrum. However, he does not discuss any specific neuroanatomical substrate for this. However, if one considers it in an evolutionary perspective, then the striatal and thalamocingulate divisions of the limbic system would be of importance. Many authors have argued for OCD being closer to psychosis @or-Henry 1973) in a late~lization model of ~ychopa~ology. Elsewhere, a case for complex motor programming deficits in OCD has been presented (Cummings and Frankel 1985) and experimentally supported (Khanna et al. 1987~). Thus, excessive repetition of such subroutines could be regarded as the basis for OCD, but animal studies have not helped in delineating exactly where this dysfunction lies. Pitman (1982) stressed the importance of the hippocampus in the genesis of OCD.
60X
UIOL PSYCHIATR? 1988:14:802-61.3
S. Khanna
Devenport et al. (198 1) reported persistance, hy~~es~nsivity, stereotypy, rituahsticlike behavior, and reduced spontaneous plasticity in the hipp~am~ctomi~d rat, all of which Pitman regarded as being very similar to compulsions. Similar effects on the rat have been found by Morris et al. (1982). However, the studies of Baxter et al. (1987) did not report any changes in this region in humans. The roIe of animal models in OCD research is questionable. The experience of obsessions is very subjective and even motor compulsions without evidence of intrusive and irrational thoughts cannot be accepted in toto as QCD models. However, MacLean’s ( 1985) model seems to agree at least in part, with psychosurgical evidence, and thus, his theoretical arguments seem to be borne out by human evidence.
Impfir Hassler and Dieckman (1973) proposed that for a thought, the specific complex mechanism is not in itself sufficient. They stressed the impartance of specific and nonspecific pathways the latter involving vigilance, directed attention, and adversion. They believed that the lower neuronal substrate for such activation was the reticular activating system whereas a higher neuronal system-the ~ncothalami~ tract-regoIated the activity of the various cortical circuits for the senses, motility, and integrative functions. In their model for OCD, disinhibition and dominance of the mediothalamic prefrontal pathways comprised the neurophysiological substrate for the “hypertrophy of conscience” in OCD. They further hypothesized that inactivation of the rostra1 intralaminar thalamic nuclei and medial thaiamic nuclei would result in relief of computsions and obsessions, respectively. Baxter et al. f 1987) have argued forcefully for the role of the caudate nuclei in OCD. Impairment of the basal ganglia has been reported to produce perseverative phenomena (Mettler 1955). The importance of the gating function of the basal ganglia in information processing has been stressed (Schneider 1984). and it is thought that when they become dysfunctional. inapprop~ate behaviorai responses can occur. The association with von Economo’s ~ncephaIitis and obsessive-compulsive symptoms tended to correlate with parkinsonian symptoms and suggested basal ganglia involvement (Bender 1935; Schilder 1938; Brickner 1940). Basal ganglia damage has also been noted in a case with OCD (Pulst et al. 1983). Isolated case reports have pointed to a lesion in the globus pallidus (Laplane et al. 1981; Ah-Cherif et al. 19843 Crey-Walter ( 1979) hypothesized that overstimulation of the cinguium led to compulsive behavior. According to Flor-Henry fI973), the obsessional syndrome was anatomically dependent on the central midline structure of the limbic system, namely, the anterior thalamic cingulate gyrus. However, he subsequently modified this view to regard OCD as a dominant frontal dysfunction (Flor-Henry et al. 1979) that was probably secondary to abno~alities in the cingulate gyrus. When there was perturbation of the dominant tem~rallimbi~ system, it resulted in a schizophrenic syndrome, whereas a manic-depressive psychosis was thought to supervene when the disorganization followed a dominant frontal-nondominant frontotemporal gradient. He also found that anterior cingulate lesions were the most effective in relieving OCD (Flor-Henry 1975). Stimulation of the cingulum has been found to result in perseverations (Meyer et al, 1973) and “obsessive” urges (Talairach et al. 1973). The phenomenon of active avoidance has been associated with the ~ingulum (1Marks f987), and this could be generalized to correlate with the resistance experienced in obsessive-compulsive phenomenon.
BIOL PSYCHL4TRY 1988;24:602-613
Obsessive-Compulsive Disorder and Frontal Lobe
609
These studies have implicated the cingulum and the basal ganglia in OCD. Cause and effect, however, are not clear, and the linkage needs to be elucidated further.
An Integration The
studies cited in this review provide tentative evidence for the involvement of the frontal lobe in OCD. Baxter et al. (1987) found higher cerebral metabolic rates in the dominant orbital gyrus, whereas Khanna et al. (1987b) reported hypofunctioning of the nondominant frontomedial region in their work on computerized electroencephalography. These two findings may appear to be contradictory but are not actually so. Serafitinides (1984) suggested in a proposed schema for cerebral lateralization of psychopathology that ruminative and verbal phenomena were more likely to occur in nondominant hemisphere dysfunction due to compensatory or release mechanisms for the rest of the brain. The issue can basically be reconciled in terms of right-left ratios; the findings of Baxter et al. (1987) and Khanna et al. (1987b) both show a change in this ratio toward dominant hemisphere functioning. Thus, it seems possible to conclude that existing evidence on the dysfunction in OCD involves the frontal lobe, with a shift in laterality to the left side. The efficacy of unilateral right-sided thalamofrontal sectioning in OCD (Hassler 1980) thus needs replication. An exact anatomical localization of this dysfunction is difficult to detail at this point in time. The similarity of the premotor and prefrontal syndromes to obsessive-compulsive phenomena and to problems in complex motor programming (Luria 1969) are striking and have already been mentioned. Similarly, lesions of the orbital gyrus result in symptoms opposite to those observed In OCD. It would be difficult to state that the dysfunction in OCD does not exist in any other part of the brain. Various pathways impinge on the frontal lobes, and their function, perforce, is dependent on this input. However, just as Muller (1985) argues for a prefrontal involvement to explain functional psychosis, the evidence reviewed here supports a frontal lobe involvement in OCD. The prefrontal cortex receives inputs from various regions, notably the cingulum, which in turn is connected to the basal ganglia. A primary dysfunction at any of these sites could easily lead to secondary dysfunctions that may mimic the (hypothesized) primary site for obsessive-compulsive symptomatology. The involvement of the cingulum in the Papez circuit for emotions may help explain the commonly observed coexistence of depression. The cause and effect relationship is difficult to differentiate. Further attempts will have to focus on patients before and after behavioral therapy (to avoid drug effects); perhaps, normals can be induced to think repetitively or to have “normal” obsessions (Rachman and deSilva 1978). Neuroanatomical correlates of an increase in obsessions by procedures like in vitro exposure (Zohar et al. 1988) or mCPP administration (Zohar and Insel 1987) are additional strategies that can be used. The current evidence provides tantalizing support for involvement of the frontal lobe in OCD, but does not answer questions about the involvement of other sites or allow us to separate cause and effect.
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