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Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation?
Medical Hypotheses (1999) 53(3), 190–193 © 1999 Harcourt Publishers Ltd Article No. mehy.1998.0744
Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation? Å. Lilja,1, 2 G. Skagerberg,2 L. G. Salford2 Departments of 1Psychiatry and 2Neurosurgery, Lund University Hospital, Lund, Sweden
Summary Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas. © 1999 Harcourt Publishers Ltd
INTRODUCTION Results from preoperative neuropsychological and neurophysiological investigations of patients with supratentorial malignant gliomas have shown that patients with high-grade gliomas, regardless of tumor site, display an inhibitory frontal lobe dysfunction with a general adynamic, concrete and inflexible attitude in the clinic. At neuropsychological testing, the patients show deficits in spatial and verbal working memory (1,2) reminiscent of the impairments of working memory seen in other studies of patients with Parkinson’s disease and in patients with frontal lobe dysfunction (3). In addition, impaired speech initative, reduced speech production concomitant with motor executive dyscontrol, features inherent in dynamic aphasia (transcortical motor aphasia) are frequent findings among our patients with high-grade gliomas (1). In spite of the fact that all patients were ignorant of the final diagnosis as regards tumor malignancy at the time of the testing, the same patients with high-grade gliomas had panic-related anxiety which the patient could not
Received 8 December 1997 Accepted 13 March 1998 Correspondence to: Dr Åsa Lilja, Department of Psychiatry, Lund University Hospital, S-221 85 Lund, Sweden
master or handle, as well as disturbances of attention, similar to those seen in patients with non-paranoid schizophrenia (4). Regional cerebral blood flow (rCBF) measurements with 133 Xe inhalation technique showed that the patients with high-grade non-frontal tumors had lower CBF distribution values in dorsal–frontal areas of the right hemisphere as well as in the left dorsal–frontal area compared to normal controls but not compared to the low-grade patients. Another interesting finding in this study was a significantly lower level of cerebral blood flow among the patients with high-grade gliomas as compared to the low-grade patients (2). The findings of frontal lobe dysfunction among patients with non-frontal high grade gliomas was repeated in a cross-validation study (5). Single photon emission computerized tomography (SPECT) with 99m-Tc HMPAO as a tracer for brain dysfunction and thallium-201 for grade of malignancy showed that the high-grade glioma patients (all had non-frontal tumors) had a selective reduction of blood flow in the dorsal and basal parts of the frontal lobes compared to the low-grade glioma group. The latter did not differ from normal subjects. The frontal decrease of blood flow correlated with the grade of malignancy of the non-frontal tumor, expressed as intensity of focal thallium-201 uptake. No correlation between tumor volume and frontal lobe blood flow reduction was found. 190
Monoaminergic dysregulation in gliomas
Paroxysmal affective experiences predominated by autonomic overactivity may have been present, perhaps before other symptoms of tumor growth in about half of the patients (6). DOPAMINE-DEPENDENT NEUROPSYCHOLOGICAL FUNCTIONS AND THE FRONTAL LOBES The stimulating function of dopamine (DA) in motor activity and learning is well described in the literature. Dopaminergic mechanisms are also involved in the regulation of arousal, attention, speech production and mood (7). Cloninger (8) ascribes the behavioral functions that are connected to dopaminergic mechanisms to a ‘behavioral activation system’, a subcortical brain network with the nucleus accumbens as a central structure. Feedback loops, involving D2 receptors, have been implicated in the regulation of self-reward and D1 in punishment or avoidance behavior. Our patients had severe deficits of attention, especially elicited under stress as well as working memory deficits, elicited in verbal as well as in spatial short-term memory tasks. Experimentally induced DA deficits in ascending dopaminergic pathways have been experimentally implicated in mediation of attentional processes and spatial working memory in the primate (9) and in patients with Parkinson’s disease. Studies have shown parkinsonian patients to be selectively impaired on neuropsycholocial tests requiring reliance on internal cues, due to executive dysfunction and attentional disturbances (3). Those experiments strongly support the view that attentional/ short-term memory are processes vulnerable to DA loss (9,10). Studies (single case and case series) of treatment with bromocriptine, a D2 receptor agonist, in neuropsychological rehabilitation of patients with acquired brain damage have shown improvement of behavioral hypoactivity manifested as psychomotor slowing, poverty of drive, lack of motivation and energy, features that are clearly compatible with the clinical picture of our patients with high-grade gliomas. Patients with non-fluent aphasia have been treated with bromocriptine. An accelerated speech production was found after treatment, indicating a role for a dopaminergic mediation in the generation of speech. As mentioned, an inhibited speech production is a frequent finding in our patients with high-grade gliomas. In human healthy subjects, treatment with bromocriptine has been shown to facilitate spatial working memory (11) in line with the results from the primate studies of Goldman–Rakic. HYPOTHESIS On the basis of our findings of reduced frontal blood flow © 1999 Harcourt Publishers Ltd
191
and behavioral disturbances including deficits in attention and working memory and also a general frontal inhibitory dysfunction reminiscent of some of the signs of schizophrenia and Parkinson’s disease, we propose that those findings in patients with malignant gliomas are attributable to a dysfunction of the central monoaminergic, in particular the dopaminergic systems. Thus, blood flow in the frontal cortex seems generally decreased in patients with Parkinson’s disease or schizophrenia; levodopa increases frontal blood flow in patients with Parkinson’s disease (12) while in normal persons cerebral blood flow within the frontal lobe, including the anterior cingulate gyrus, is increased by the DA agonist apomorphine (13) while amphetamine also normalizes CBF in task-dependent activation of the latter structure in schizophrenics (14). Although it is well established that severe DA deficiency in the basal ganglia constitutes a primary defect in Parkinson’s disease, the role of DA in schizophrenia, while in all probability of primary importance, appears much more complex, with recent evidence speaking in favour of hypoactivity of the DA system in the anterior cingulate cortex and a hyperactivity in subcortical areas (15). Furthermore, the finding of dosedependent differential effects on working memory of DA receptor stimulation (16) supports the notion that undue fluctuations in DA levels may cause behavioral and cognitive, DA-dependent, impairment which, however, is not simply related to either constant lack or excess of dopamine. At the cellular level, several mechanisms are possible, and in our view in fact likely, by which disordered glial function might cause undue fluctuations of transmitterlevels in patients with malignant gliomas. Abnormal expression of transmitter-related receptors in transformed glial cells may in turn further aggravate the functional consequences of such fluctuations. In normal circumstances, there is a well-regulated, partly receptormediated, co-operation between glia and neurons serving to maintain optimal perineuronal concentrations of transmitters, electrolytes and metabolic substrates (17). Glially located transporters for excitatory amino acids and GABA have been known for a long time – these are important for keeping transmitterlevels within physiological range and for terminating their action upon neuronal and glial receptors. While transporter-mediated release of neurotransmitters (reverse transport) may sometimes be essential for the normal inhibitory action of GABA (18)-impaired regulation of such transporters may cause inappropriate release of various transmitters (17). Recently, such transporters has been described also for monoamines including DA (19), since these transporters are expressed also in stem cells of the subventricular zone (20), it seems reasonable to conceive that as such they may be abnorMedical Hypotheses (1999) 53(3), 190–193
192
Lilja et al.
mally expressed in malignant cells, thereby causing a dysregulation of extracellular transmitter levels. Tumor-dependent differential expression or modulation of enzymes involved in synthesis or degradation of transmitter (21) provides another mechanism for aberrant transmission. One such enzyme is MAO-B, which is important for the degradation of DA and which is preferentially found in glia cells (22). Preliminary results from our group indicate that MAO-B activity is changed within malignant gliomas (unpublished data). Dysregulation of extracellular transmitter concentration could, through action on neuronal autoreceptors, secondarily affect both transmitter synthesis and release. Thus, it is well known that both dopamine synthesis and release as well as the synthesis of dopamine receptors themselves are normally partly regulated by autoreceptors (23). Rapid tumor growth may also constitute a competition for substrate for transmitter synthesis. Rate-limiting substrate dependendence has been most thoroughly described and studied for serotonin, in which case tryptophan depletion has been shown to have behavioral effects in humans (24) but also brain catecholamine biosynthesis are known to be controlled by brain tyrosine concentration (25). Our patients with high-grade gliomas showed inability to handle stress and anxiety. A few early stress experiments with animals have shown uncontrollable stressors to change DA activity. Dopamine neural activity has been found to be altrered by stressors in the arcuate nucleus and the lateral septal region of the thalamus, in mesolimbic frontal cortex as well as the nucleus accumbens (26). It has also been shown that the activity of mesocortico-frontal dopaminergic neurons is reduced after stress (27). The presenting symptoms of paroxysmal affective disturbances, and at later stages lack of psychological control over stressful situations, may thus be both caused by and further aggravated by the primary DA dysregulation induced by the transformed glia cell population present in these patients. CONCLUDING REMARKS The proposed hypothesis implying disordered dopaminergic transmission as a generalized underlying cause for neuropsychological dysfunction in patients with malignant gliomas suggests that the possibilities of improving the situation for the patient with pharmacological agents with actions on the frontal dopaminergic systems should be explored. Furthermore, the hypothesis implies that neurotransmission in other systems may be similarly dysregulated; if this could be corroborated, several possibilities for pharmacological or perhaps dietary intervention may exist which, in conjunction with Medical Hypotheses (1999) 53(3), 190–193
conventional treatment regimes, could further optimize the situation for these patients.
ACKNOWLEDGEMENTS This research was supported by grants from the Swedish Cancer Society projects#3459-B93-01XAC, #3459-B96-04XAB, the Swedish National Board of Health and Wellfare, the Medical Faculty of Lund University as well as the research foundations of Bertha Kamprad and Lund Sjukvårdsdistrikt.
REFERENCES 1. Lilja Å., Salford L. G., Smith G. J. W., et al. Neuropsychological indexes of a partial ‘frontal syndrome’ in patients with nonfrontal gliomas. Neuropsychology 1992; 4: 315–326. 2. Lilja Å., Hagstadius S., Risberg J., Salford L. G., Smith G. J. W., Öhman R. Frontal lobe dynamics in brain tumor patients: a study of regional cerebral blood flow and affective changes before and after surgery. Neuropsychiatr Neurpsychol Behav Neurol 1992; 5: 294–300. 3. Lange K. W., Robbins T. W., Marsden C. D., James M., Owen A. M., Paul G. M. L-dopa withdrawal in patients with Parkinsons disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology 1992; 107: 394–404. 4. Lilja Å., Smith G. J. W., Salford L. G. Microprocesses in perception and personality. J Nerv Ment Dis 1992; 2: 82–88. 5. Lilja Å., Sjöholm H., Rosen I., Salford L. G. High grade nonfrontal gliomas are associated with frontal hypoperfusion on SPECT and behavioral disturbances of frontal networks. J Neuro-oncol submitted. 6. Lilja Å., Salford L. G. Early mental changes in patients with astrocytomas with special reference to anxiety and epilepsia. Psychopathology, in press. 7. Beninger R. J. The role of dopamine in locomotor activity and learning. Brain Res Rev 1983; 6: 173–196. 8. Cloninger C. R. Brain networks underlying personality development. In: Caroll B. J., Barett J. E. (eds). Psychopathology and the Brain. New York: Raven Press 1991: 183–204. 9. Goldman-Rakic P. S. Dopamine-mediated mechanisms of the prefrontal cortex. Sem Neurosci 1992; 4: 149–150. 10. Toshiyuki S., Goldman-Rakic P. S. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991; 251: 947–950. 11. Müller U., Cramon Y. The therapeutic potential of bromocriptine in neuropschological rehabilitation of patients with acquired brain damage. Progr Neuro-Psychopharmacol Biol Psychiat 1994; 18: 1103–1120. 12. Kobari M., Fukuuchi Y., Shinohara T., Obara K., Nagawa S. Levodopa-induced local cerebral blood flow changes in Parkinson’s disease and related disorders. J Neurol Sci 1995; 128: 212–218. 13. Grasby P. M., Friston K. J., Bench C. J., et al. The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers. Psychol Med 1993; 23: 605–612. 14. Daniel D. G., Weinberger D. R., Jones D. W. et al. The effect of amphetamine on regional cerebral blood flow during dognitive activation in schizophrenia. J Neurosci 1991; 11: 1907–1917. 15. Jaskiw G. E., Weinberger D. R. Dopamine and schizophrenia – a cortically corrective perspective. Sem Neurosci 1992; 4: 179–188.
© 1999 Harcourt Publishers Ltd
Monoaminergic dysregulation in gliomas
16. Williams G. V., Goldman-Rakic P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995; 376: 572–575. 17. Sontheimer H. Glial influences on neuronal signaling. The Neuroscientist 1995; 1: 123–126. 18. During J. M., Ryder M. K., Spencer D. D. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 1995; 376: 174–177. 19. Kitayama S., Dohi T. Cellular and molecular aspects of monoamine neurotransmitter transporters. Jpn J Pharmacol 1996; 72: 195–208. 20. Xu W., Emson P. C. Neuronal stem cells express vesicular monoamine transporter 2 immunoreactivity in the adult rat. Neuroscience 1997; 76: 7–10. 21. Abell C. W. Synthesis, function, and degradation of catecholamine neurotransmitters. In: van Ree J. M., Mathysse S. (eds). Progress in Brain Research vol. 65. Amsterdam: Elsevier Science Publishers, 1986: 139–152.
© 1999 Harcourt Publishers Ltd
193
22. Student A. K., Edwards D. J. Subcellular localization of type A and B monoamine oxidase in rat brain. Biochem Pharmacol 1977; 209: 339–354. 23. Jaber M., Robinson S. W., Missale C., Caron M. G. Dopamine receptors and brain function. Neuropharmacol 1996; 35: 1503–1519. 24. Smith K. A., Fairburn C. G., Cowen P. J. Relapse of depression after rapid depletion of tryptophan. Lancet 1997; 349: 915–919. 25. Wurtman R. J., Larin F. Mostafapour S., Fernstrom J. D. Brain catecholamine synthesis: control by brain tyrosine concentration. Science 1974; 185: 183–184. 26. Anisman H., Zacharko R. M. Stress and neoplasia. Speculations and caveats. Behav Med Update 1983; 5: 27–35. 27. Blanc G., Hervé D., Simon H., Lisoprawski A., Glowinski J., Tassin J. P. Response to stress of mesocortico-frontal dopaminergic neurones in rats ofter long-term isolation. Nature 1980; 284: 265–267.
Medical Hypotheses (1999) 53(3), 190–193
Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation? Å. Lilja,1, 2 G. Skagerberg,2 L. G. Salford2 Departments of 1Psychiatry and 2Neurosurgery, Lund University Hospital, Lund, Sweden
Summary Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas. © 1999 Harcourt Publishers Ltd
INTRODUCTION Results from preoperative neuropsychological and neurophysiological investigations of patients with supratentorial malignant gliomas have shown that patients with high-grade gliomas, regardless of tumor site, display an inhibitory frontal lobe dysfunction with a general adynamic, concrete and inflexible attitude in the clinic. At neuropsychological testing, the patients show deficits in spatial and verbal working memory (1,2) reminiscent of the impairments of working memory seen in other studies of patients with Parkinson’s disease and in patients with frontal lobe dysfunction (3). In addition, impaired speech initative, reduced speech production concomitant with motor executive dyscontrol, features inherent in dynamic aphasia (transcortical motor aphasia) are frequent findings among our patients with high-grade gliomas (1). In spite of the fact that all patients were ignorant of the final diagnosis as regards tumor malignancy at the time of the testing, the same patients with high-grade gliomas had panic-related anxiety which the patient could not
Received 8 December 1997 Accepted 13 March 1998 Correspondence to: Dr Åsa Lilja, Department of Psychiatry, Lund University Hospital, S-221 85 Lund, Sweden
master or handle, as well as disturbances of attention, similar to those seen in patients with non-paranoid schizophrenia (4). Regional cerebral blood flow (rCBF) measurements with 133 Xe inhalation technique showed that the patients with high-grade non-frontal tumors had lower CBF distribution values in dorsal–frontal areas of the right hemisphere as well as in the left dorsal–frontal area compared to normal controls but not compared to the low-grade patients. Another interesting finding in this study was a significantly lower level of cerebral blood flow among the patients with high-grade gliomas as compared to the low-grade patients (2). The findings of frontal lobe dysfunction among patients with non-frontal high grade gliomas was repeated in a cross-validation study (5). Single photon emission computerized tomography (SPECT) with 99m-Tc HMPAO as a tracer for brain dysfunction and thallium-201 for grade of malignancy showed that the high-grade glioma patients (all had non-frontal tumors) had a selective reduction of blood flow in the dorsal and basal parts of the frontal lobes compared to the low-grade glioma group. The latter did not differ from normal subjects. The frontal decrease of blood flow correlated with the grade of malignancy of the non-frontal tumor, expressed as intensity of focal thallium-201 uptake. No correlation between tumor volume and frontal lobe blood flow reduction was found. 190
Monoaminergic dysregulation in gliomas
Paroxysmal affective experiences predominated by autonomic overactivity may have been present, perhaps before other symptoms of tumor growth in about half of the patients (6). DOPAMINE-DEPENDENT NEUROPSYCHOLOGICAL FUNCTIONS AND THE FRONTAL LOBES The stimulating function of dopamine (DA) in motor activity and learning is well described in the literature. Dopaminergic mechanisms are also involved in the regulation of arousal, attention, speech production and mood (7). Cloninger (8) ascribes the behavioral functions that are connected to dopaminergic mechanisms to a ‘behavioral activation system’, a subcortical brain network with the nucleus accumbens as a central structure. Feedback loops, involving D2 receptors, have been implicated in the regulation of self-reward and D1 in punishment or avoidance behavior. Our patients had severe deficits of attention, especially elicited under stress as well as working memory deficits, elicited in verbal as well as in spatial short-term memory tasks. Experimentally induced DA deficits in ascending dopaminergic pathways have been experimentally implicated in mediation of attentional processes and spatial working memory in the primate (9) and in patients with Parkinson’s disease. Studies have shown parkinsonian patients to be selectively impaired on neuropsycholocial tests requiring reliance on internal cues, due to executive dysfunction and attentional disturbances (3). Those experiments strongly support the view that attentional/ short-term memory are processes vulnerable to DA loss (9,10). Studies (single case and case series) of treatment with bromocriptine, a D2 receptor agonist, in neuropsychological rehabilitation of patients with acquired brain damage have shown improvement of behavioral hypoactivity manifested as psychomotor slowing, poverty of drive, lack of motivation and energy, features that are clearly compatible with the clinical picture of our patients with high-grade gliomas. Patients with non-fluent aphasia have been treated with bromocriptine. An accelerated speech production was found after treatment, indicating a role for a dopaminergic mediation in the generation of speech. As mentioned, an inhibited speech production is a frequent finding in our patients with high-grade gliomas. In human healthy subjects, treatment with bromocriptine has been shown to facilitate spatial working memory (11) in line with the results from the primate studies of Goldman–Rakic. HYPOTHESIS On the basis of our findings of reduced frontal blood flow © 1999 Harcourt Publishers Ltd
191
and behavioral disturbances including deficits in attention and working memory and also a general frontal inhibitory dysfunction reminiscent of some of the signs of schizophrenia and Parkinson’s disease, we propose that those findings in patients with malignant gliomas are attributable to a dysfunction of the central monoaminergic, in particular the dopaminergic systems. Thus, blood flow in the frontal cortex seems generally decreased in patients with Parkinson’s disease or schizophrenia; levodopa increases frontal blood flow in patients with Parkinson’s disease (12) while in normal persons cerebral blood flow within the frontal lobe, including the anterior cingulate gyrus, is increased by the DA agonist apomorphine (13) while amphetamine also normalizes CBF in task-dependent activation of the latter structure in schizophrenics (14). Although it is well established that severe DA deficiency in the basal ganglia constitutes a primary defect in Parkinson’s disease, the role of DA in schizophrenia, while in all probability of primary importance, appears much more complex, with recent evidence speaking in favour of hypoactivity of the DA system in the anterior cingulate cortex and a hyperactivity in subcortical areas (15). Furthermore, the finding of dosedependent differential effects on working memory of DA receptor stimulation (16) supports the notion that undue fluctuations in DA levels may cause behavioral and cognitive, DA-dependent, impairment which, however, is not simply related to either constant lack or excess of dopamine. At the cellular level, several mechanisms are possible, and in our view in fact likely, by which disordered glial function might cause undue fluctuations of transmitterlevels in patients with malignant gliomas. Abnormal expression of transmitter-related receptors in transformed glial cells may in turn further aggravate the functional consequences of such fluctuations. In normal circumstances, there is a well-regulated, partly receptormediated, co-operation between glia and neurons serving to maintain optimal perineuronal concentrations of transmitters, electrolytes and metabolic substrates (17). Glially located transporters for excitatory amino acids and GABA have been known for a long time – these are important for keeping transmitterlevels within physiological range and for terminating their action upon neuronal and glial receptors. While transporter-mediated release of neurotransmitters (reverse transport) may sometimes be essential for the normal inhibitory action of GABA (18)-impaired regulation of such transporters may cause inappropriate release of various transmitters (17). Recently, such transporters has been described also for monoamines including DA (19), since these transporters are expressed also in stem cells of the subventricular zone (20), it seems reasonable to conceive that as such they may be abnorMedical Hypotheses (1999) 53(3), 190–193
192
Lilja et al.
mally expressed in malignant cells, thereby causing a dysregulation of extracellular transmitter levels. Tumor-dependent differential expression or modulation of enzymes involved in synthesis or degradation of transmitter (21) provides another mechanism for aberrant transmission. One such enzyme is MAO-B, which is important for the degradation of DA and which is preferentially found in glia cells (22). Preliminary results from our group indicate that MAO-B activity is changed within malignant gliomas (unpublished data). Dysregulation of extracellular transmitter concentration could, through action on neuronal autoreceptors, secondarily affect both transmitter synthesis and release. Thus, it is well known that both dopamine synthesis and release as well as the synthesis of dopamine receptors themselves are normally partly regulated by autoreceptors (23). Rapid tumor growth may also constitute a competition for substrate for transmitter synthesis. Rate-limiting substrate dependendence has been most thoroughly described and studied for serotonin, in which case tryptophan depletion has been shown to have behavioral effects in humans (24) but also brain catecholamine biosynthesis are known to be controlled by brain tyrosine concentration (25). Our patients with high-grade gliomas showed inability to handle stress and anxiety. A few early stress experiments with animals have shown uncontrollable stressors to change DA activity. Dopamine neural activity has been found to be altrered by stressors in the arcuate nucleus and the lateral septal region of the thalamus, in mesolimbic frontal cortex as well as the nucleus accumbens (26). It has also been shown that the activity of mesocortico-frontal dopaminergic neurons is reduced after stress (27). The presenting symptoms of paroxysmal affective disturbances, and at later stages lack of psychological control over stressful situations, may thus be both caused by and further aggravated by the primary DA dysregulation induced by the transformed glia cell population present in these patients. CONCLUDING REMARKS The proposed hypothesis implying disordered dopaminergic transmission as a generalized underlying cause for neuropsychological dysfunction in patients with malignant gliomas suggests that the possibilities of improving the situation for the patient with pharmacological agents with actions on the frontal dopaminergic systems should be explored. Furthermore, the hypothesis implies that neurotransmission in other systems may be similarly dysregulated; if this could be corroborated, several possibilities for pharmacological or perhaps dietary intervention may exist which, in conjunction with Medical Hypotheses (1999) 53(3), 190–193
conventional treatment regimes, could further optimize the situation for these patients.
ACKNOWLEDGEMENTS This research was supported by grants from the Swedish Cancer Society projects#3459-B93-01XAC, #3459-B96-04XAB, the Swedish National Board of Health and Wellfare, the Medical Faculty of Lund University as well as the research foundations of Bertha Kamprad and Lund Sjukvårdsdistrikt.
REFERENCES 1. Lilja Å., Salford L. G., Smith G. J. W., et al. Neuropsychological indexes of a partial ‘frontal syndrome’ in patients with nonfrontal gliomas. Neuropsychology 1992; 4: 315–326. 2. Lilja Å., Hagstadius S., Risberg J., Salford L. G., Smith G. J. W., Öhman R. Frontal lobe dynamics in brain tumor patients: a study of regional cerebral blood flow and affective changes before and after surgery. Neuropsychiatr Neurpsychol Behav Neurol 1992; 5: 294–300. 3. Lange K. W., Robbins T. W., Marsden C. D., James M., Owen A. M., Paul G. M. L-dopa withdrawal in patients with Parkinsons disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology 1992; 107: 394–404. 4. Lilja Å., Smith G. J. W., Salford L. G. Microprocesses in perception and personality. J Nerv Ment Dis 1992; 2: 82–88. 5. Lilja Å., Sjöholm H., Rosen I., Salford L. G. High grade nonfrontal gliomas are associated with frontal hypoperfusion on SPECT and behavioral disturbances of frontal networks. J Neuro-oncol submitted. 6. Lilja Å., Salford L. G. Early mental changes in patients with astrocytomas with special reference to anxiety and epilepsia. Psychopathology, in press. 7. Beninger R. J. The role of dopamine in locomotor activity and learning. Brain Res Rev 1983; 6: 173–196. 8. Cloninger C. R. Brain networks underlying personality development. In: Caroll B. J., Barett J. E. (eds). Psychopathology and the Brain. New York: Raven Press 1991: 183–204. 9. Goldman-Rakic P. S. Dopamine-mediated mechanisms of the prefrontal cortex. Sem Neurosci 1992; 4: 149–150. 10. Toshiyuki S., Goldman-Rakic P. S. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991; 251: 947–950. 11. Müller U., Cramon Y. The therapeutic potential of bromocriptine in neuropschological rehabilitation of patients with acquired brain damage. Progr Neuro-Psychopharmacol Biol Psychiat 1994; 18: 1103–1120. 12. Kobari M., Fukuuchi Y., Shinohara T., Obara K., Nagawa S. Levodopa-induced local cerebral blood flow changes in Parkinson’s disease and related disorders. J Neurol Sci 1995; 128: 212–218. 13. Grasby P. M., Friston K. J., Bench C. J., et al. The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers. Psychol Med 1993; 23: 605–612. 14. Daniel D. G., Weinberger D. R., Jones D. W. et al. The effect of amphetamine on regional cerebral blood flow during dognitive activation in schizophrenia. J Neurosci 1991; 11: 1907–1917. 15. Jaskiw G. E., Weinberger D. R. Dopamine and schizophrenia – a cortically corrective perspective. Sem Neurosci 1992; 4: 179–188.
© 1999 Harcourt Publishers Ltd
Monoaminergic dysregulation in gliomas
16. Williams G. V., Goldman-Rakic P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995; 376: 572–575. 17. Sontheimer H. Glial influences on neuronal signaling. The Neuroscientist 1995; 1: 123–126. 18. During J. M., Ryder M. K., Spencer D. D. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 1995; 376: 174–177. 19. Kitayama S., Dohi T. Cellular and molecular aspects of monoamine neurotransmitter transporters. Jpn J Pharmacol 1996; 72: 195–208. 20. Xu W., Emson P. C. Neuronal stem cells express vesicular monoamine transporter 2 immunoreactivity in the adult rat. Neuroscience 1997; 76: 7–10. 21. Abell C. W. Synthesis, function, and degradation of catecholamine neurotransmitters. In: van Ree J. M., Mathysse S. (eds). Progress in Brain Research vol. 65. Amsterdam: Elsevier Science Publishers, 1986: 139–152.
© 1999 Harcourt Publishers Ltd
193
22. Student A. K., Edwards D. J. Subcellular localization of type A and B monoamine oxidase in rat brain. Biochem Pharmacol 1977; 209: 339–354. 23. Jaber M., Robinson S. W., Missale C., Caron M. G. Dopamine receptors and brain function. Neuropharmacol 1996; 35: 1503–1519. 24. Smith K. A., Fairburn C. G., Cowen P. J. Relapse of depression after rapid depletion of tryptophan. Lancet 1997; 349: 915–919. 25. Wurtman R. J., Larin F. Mostafapour S., Fernstrom J. D. Brain catecholamine synthesis: control by brain tyrosine concentration. Science 1974; 185: 183–184. 26. Anisman H., Zacharko R. M. Stress and neoplasia. Speculations and caveats. Behav Med Update 1983; 5: 27–35. 27. Blanc G., Hervé D., Simon H., Lisoprawski A., Glowinski J., Tassin J. P. Response to stress of mesocortico-frontal dopaminergic neurones in rats ofter long-term isolation. Nature 1980; 284: 265–267.
Medical Hypotheses (1999) 53(3), 190–193