Since the vagus is a mixed nerve, VNS always comprises a portion of efferent stimulation which may alter peripheral functions. For instance, it may cause hoarseness as the most common adverse effect of VNS. As a matter of course, any changes concerning mood or epileptic seizures must be due to cerebral changes. However, from a theoretical point of view one has good reasons to expect that peripheral changes induced by efferent VNS may in turn result in cerebral changes relevant for the issues discussed here.
In mammalians the efferent branch of the vagus plays a decisive role in emotion regulation and expression (Porges 1997; Porges et al., 1994). Furthermore, the vagus is supposed to coordinate and protect the organism's metabolic resources, e.g. by retarding heart rate more or less ('vagal brake') (Porges, 1995). This more theoretical view is confirmed by clinical observations in neuropsychiatric disorders such as depression and anxiety which reveal clear associations between mood and parasympathetic functions (Glassman, 1998; Lehofer et al., 1997, 1999). Diurnal mood variations in some depressed patients may be associated with parasympa-thetic activity (Rechlin et al., 1995). Regarding cardiac measures, it is noteworthy that there is no evidence for altered vagal tone in unmedicated clinical depressions but for increased sympathetic tone (heart rate) which may be due to increased anxiety in depressed patients (Lehofer et al., 1997; Yeragani et al., 1991). Interestingly, experimentally induced panic attacks (hyperventilation, sodium lactate administration) are accompanied by an attenuated vagal tone (George et al., 1989) suggesting that anxiety disorders may be even more susceptible for VNS treatment than depressions. Other authors have also suggested a linkage between vagal functions and anxiety disorders (Watkins et al., 1998).
In animal experiments, one can transiently block efferent neural transmission by a lidocaine injection below the point of electrical stimulation (Brodin, 1985). In such an experiment, Clark et al. (1998) could show that effects on retention and recognition exclusively resulted from the afferent portion of VNS. Investigating the role of efferent vagal transmission in patients is difficult. One would have to record peripheral physiological measures and consider them as covariates during data analysis. Even if there is no evidence for general alterations of cardiac or gastrointestinal functions due to VNS in the sense of adverse effects (Ramsay et al., 1994), peripheral changes induced by VNS may be small and more difficult to register.
In the Elger et al. (2000) study, mood improvements were particularly expressed in a reduction of negative symptoms as recorded by the Scale for the Assessment of Negative Symptoms (Andreasen, 1981) or by the anergia scale of the Brief Psychiatric Rating Scale (Overall and Gorham, 1962). We propose that negative symptoms and particularly anergia may be interpreted as a lack of energy in which the autonomic nervous system and particularly the vagus may be involved.
Preliminary data of our on-going self-report questionnaire study suggest that VNS improves 'anxiety' and 'unpleasant exertion' as recorded by the Self-Rating Anxiety Scale (Zung, 1971) or the Befindlichkeits-Skala (Zerssen et al., 1970). In contrast, improvement of depressed mood, which was measured by the Beck Depression Inventory, appears to be a smaller effect. One has to consider that this self-report questionnaire particularly accounts for higher cognitive and emotional aspects of depression. Therefore, we assume that efferent VNS may contribute to mood improvements, first and more unspecifically, by tuning the basic autonomic balance and the vagal management of metabolic resources, or second and more specifically, by attenuating sympathetic tone and peripheral symptoms of anxiety.
Finally, we would like to allude to some theoretical difficulties associated with the fact that the vagus is more part of a 'system' than two 'one-way routes': VNS has an impact on the entire vagal brain-periphery feedback loop and electrical stimulation affects signalling in both directions. A vagus under VNS may make the brain 'think' that peripheral functions have changed - even if they actually have not, that is, even if no objective changes can be revealed by psychophysiological measurements. Such a mechanism could be described as virtually peripheral. Conversely, VNS may distort or suggest commands coming from the brain which are to be transmitted to the periphery by the vagus. This virtually cerebral mechanism results in peripheral effects, as for example hoarseness. Studies on the alterations of neural transmission within the vagus as induced by VNS would be required. So far, the artificial stimulation of the vagal system by VNS - with its unphysiological duty cycles, output currents and pulse frequencies - has to be regarded as very coarse. In fact, some authors assume that this is the true reason why more serious cardiac side effects do not occur in patients under VNS (George et al., 2000). A better understanding of vagal neurotransmission will provide the basis for more subtle, more adaptive and hopefully even more effective brain stimulation techniques in the future. VNS is probably the promising beginning of this intriguing development and an important scientific tool for human research on these issues.
Amar, A.P., DeGiorgio, C.M., Tarver, W.B. and Apuzzo, M.L. (1999). Long-term multicenter experience with vagus nerve stimulation for intractable partial seizures: results of the XE5 trial. Stereotact Funct Neurosurg, 73, 104-8.
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) (DSM-IV). Washington, DC: APA.
Andreasen, N.C. (1981). Scale for the Assessment of Negative Symptoms (SANS). Iowa City: University of Iowa.
Annegers, J.F., Coan, S.P., Hauser, W.A., Leetsma, J., Duffell, W. and Tarver, B. (1998). Epilepsy, vagal nerve stimulation by the NCP system, mortality, and sudden, unexpected, unexplained death. Epilepsia, 39, 206-12.
Bailey, P. and Bremer, F. (1938). A sensory cortical representation of the vagus nerve. J Neurophysiology, 1, 405-12.
Beck, A.T. (1967). Depression: Clinical, Experimental, and Theoretical Aspects. New York: Hoeber.
Ben-Menachem, E., Manon Espaillat, R., Ristanovic, R. et al. (1994). Vagus nerve stimulation for treatment of partial seizures, 1. A controlled study of effect on seizures (First International Vagus Nerve Stimulation Study Group). Epilepsia, 35, 616-26.
Ben-Menachem, E., Hamberger, A., Hedner, T. et al. (1995). Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res, 20, 221-7.
Boon, P., Vonck, K., D'Have, M., O'Connor, S., Vandekerckhove, T. and De Reuck, J. (1999). Cost-benefit of vagus nerve stimulation for refractory epilepsy. Acta Neurol Belg, 99, 275-80.
Brodin, P. (1985). Differential inhibition of A, B and C fibres in the rat vagus nerve by lidocaine, eugenol and formaldehyde. Arch Oral Biol, 30, 477-80.
Calabrese, J.R., Bowden, C.L., Sachs, G.S., Ascher, J.A., Monaghan, E. and Rudd, G.D. (1999). A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatr, 60, 79-88.
Clark, K.B., Smith, D.C., Hassert, D.L., Browning, R.A., Naritoku, D.K. and Jensen, R.A. (1998). Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactiva-tion enhances memory storage processes in the rat. Neurobiol Learning Memory, 70, 364-73.
Clark, K.B., Naritoku, D.K., Smith, D.C., Browning, R.A. and Jensen, R.A. (1999). Enhanced recognition memory following vagus nerve stimulation in human subjects. Nature Neurosci, 2, 94-8.
DeGiorgio, C.M., Schachter, S.C., Handforth, A. et al. (2000). Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia, 41, 1195-200.
Elger, G., Hoppe, C., Falkai, P., Rush, A.J. and Elger, C.E. (2000). Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res, 42, 203-10.
Fisher, R.S. and Handforth, A. (1999). Reassessment: Vagus nerve stimulation for epilepsy: A report of the Therapeutics and Technology Assessment Subcommittee for the American Academy of Neurology. Neurology, 53, 666-9.
Foley, J.O. and DuBois, F. (1937). Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory and motor studies. J Comp Neurol, 67, 49-67.
George, D.T., Nutt, D.J., Walker, W.V., Porges, S.W., Adinoff, B. and Linnoila, M. (1989). Lactate and hyperventilation substantially attenuate vagal tone in normal volunteers. Arch Gen Psychiatry, 46, 153-6.
George, M.S., Sackheim, H.A., Rush, J.A. et al. (2000). Vagus nerve stimulation: a new tool for brain research and therapy. J Biol Psychiatry, 47, 287-95.
Glassman, A.H. (1998). Depression, cardiac death, and the central nervous system. Neuropsychobiology, 37, 80-3.
Hamilton, M. (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry, 12, 371-9.
Hamilton, M. (1967). Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol, 6, 278-96.
Hammond, E.J., Uthman, B.M., Reid, S.A. and Wilder, B.J. (1992a). Electrophysiological studies of cervical vagus nerve stimulation in humans: I. EEG effects. Epilepsia, 33, 1013-20.
Hammond, E.J., Uthman, B.M., Wilder, B.J. et al. (1992b). Neurochemical effects of vagus nerve stimulation in humans. Brain Res, 583, 300-3.
Handforth, A., DeGiorgio, C.M., Schachter, S.C. et al. (1998). Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology, 51, 48-55.
Harden, C.L., Lazar, L.M., Pick, L.H. et al. (1999). A beneficial effect on mood in partial epilepsy patients treated with gabapentin. Epilepsia, 40, 1129-34.
Harden, C.L., Pulver, M.C., Ravdin, L.D., Nikolov, B., Halper, J.P. and Labar, D.R. (2000). A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav, 1, 93-9.
Henry, T.R., Bakay, R.A.E., Votaw, J.R. et al. (1998). Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: acute effects at high and low levels of stimulation. Epilepsia, 39, 983-90.
Henry, T.R., Votaw, J.R., Pennell, P.B. et al. (1999). Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy. Neurology, 52, 1166-73.
Hermann, B.P., Trenerry, M.R. and Colligan, R.C. (1996). Learned helplessness attributional style and depression in epilepsy (Bozeman Epilepsy Surgery Consortium). Epilepsia, 37, 680-6.
Jacoby, A., Baker, G.A., Stehen, N., Potts, P. and Chadwick, D.W. (1996). The clinical course of epilepsy and its psychosocial correlates: findings from a UK Community study. Epilepsia, 37, 148-61.
Kohler, C., Norstrand, J.A., Baltuch, G. et al. (1999). Depression in temporal lobe epilepsy before epilepsy surgery. Epilepsia, 40, 336-40.
Krahl, S.E., Clark, K.B., Smith, D.C. and Browning, R.A. (1998). Locus coeruleus lesions suppress the seizure attenuating effects of vagus nerve stimulation. Epilepsia, 39, 709-14.
Krahl, S.E., Senanayake, S.S. and Handforth, A. (2000). Seizure suppression by systemic epinephrine is mediated by the vagus nerve. Epilepsy Res, 38, 171-5.
Lehofer, M., Moser, M., Hoehn-Saric, R. et al. (1997). Major depression and cardiac autonomic control. Biol Psychiatry, 42, 914-19.
Lehofer, M., Moser, M., Hoehn-Saric, R. et al. (1999). Influence of age on the parasympatholytic property of tricyclic antidepressants. Psychiatry Res, 85, 199-207.
Letterman, L. and Markowitz, J.S. (1999). Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions. Pharmacotherapy, 19, 565-72.
Mason, B., Kocsis, J., Leon, A. et al. (1993). Measurement of severity and treatment response in dysthymia. Psychiatr Ann, 23, 625-31.
Montgomery, S.A. and Asberg, M. (1979). A new depression scale designed to be sensitive to change. Br J Psychiatry, 134, 382-9.
Naritoku, D.K., Terry, W.J. and Helfert, R.H. (1995). Regional induction of Fos immunoreactiv-ity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res, 22, 53-62.
O'Donoghue, M.F., Goodridge, D.M., Redhead, K., Sander, J.W. and Duncan, J.S. (1999). Assessing the psychosocial consequences of epilepsy. A community-based study. Br J Gen Pract, 49, 211-14.
Okuma, T., Kishimoto, A., Inoue, K., Matsumoto, H. and Ogura, A. (1973). Anti-manic and prophylactic effects of carbamazepine (Tegretol) on manic depressive psychosis. A preliminary report. Folia Psychiatr Neurol Jpn, 27, 283-97.
Olfson, M., Marcus, S., Sackheim, H.A., Thophson, J. and Pincus, H.A. (1998). Use of ECT for the inpatient treatment of recurrent major depression. Am J Psychiatry, 155, 22-9.
Overall, J.E. and Gorham, D.R. (1962). The Brief Psychiatric Rating Scale. Psychol Rep, 10, 799-812.
Penry, J.K. and Dean, J.C. (1990). Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results (Abstract). Epilepsy, 31 (Suppl.), S40-3.
Porges, S.W. (1995). Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A polyvagal theory. Psychophysiology, 32, 301-18.
Porges, S.W. (1997 ). Emotion: an evolutionary by-product of the neural regulation of the autonomic nervous system. Ann New York Acad Sci, USA, 807, 62-77.
Porges, S.W., Doussard-Roosevelt, J.A. and Maiti, A.K. (1994). Vagal tone and the physiological regulation of emotion. Monogr Soc Res Child Dev, 59, 167-86.
Post, R.M., Weiss, S.R.B. and Chuang, D.M. (1992). Mechanisms of action of anticonvulsant in affective disorders: comparisons with lithium. J Clin Psychopharmacol, 12 (Suppl. 1), S23-35.
Ramsay, R.E., Uthman, B.M., Augustinsson, L.E. et al. (1994). Vagus nerve stimulation for treatment of partial seizures, 2. Safety side effects and tolerability (First International Vagus Nerve Stimulation Study Group). Epilepsia, 35, 627-36.
Rechlin, T., Weis, M. and Kaschka, W.P. (1995). Is diurnal variation of mood associated with parasympathetic activity? J Affect Disord, 34, 249-55.
Regenold, W.T., Weintraub, D. and Taller, A. (1998). Electroconvulsive therapy for epilepsy and major depression. Am J Geriatr Psychiatry, 6, 180-3.
Roth, D.L., Goode, K.T., Williams, V.L. and Faught, E. (1994). Physical exercise, stressful life experience and depression in adults with epilepsy. Epilepsia, 35, 1248-55.
Rush, A.J., George, M.S., Sackheim, H.A. et al. (2000). Vagus nerve stimulation (VNS) for treatment-resistant depression, a multicenter study. J Biol Psychiatry, 47, 276-86.
Rutecki, P. (1990). Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia, 31, S1-6.
Sackheim, H.A. (1999). The anticonvulsant hypothesis of the mechanism of action of ECT, current status. J ECT, 15, 5-26.
Sackheim, H.A., Decina, P., Malitz, S., Reesor, S.R. and Prohovnik, I. (1983). Anticonvulsant and antidepressant properties of electroconvulsive therapy, a proposed mechanism of action. Biol Psychiatry, 18, 1301-10.
Sackheim, H.A., Luber, B., Katzman, G.P. et al. (1996). The effects of electroconvulsive therapy on quantitative electroencephalograms, relationship to clinical outcome. Arch Gen Psychiatry, 53, 814-24.
Schachter, S.C. and Saper, C.B. (1998). Vagus nerve stimulation. Epilepsia, 39, 677-86.
Schatzberg, A.F. and Schildkraut, J.J. (1996). Recent studies on norepinephrine systems in mood disorders. In Psychopharmacology, 4th Generation of Progress, ed. F. Bloom and D. Kupfer, pp. pp. 911-20. New York: Raven Press.
Schmitz, E.B., Robertson, M.M. and Trimble, M.R. (1999). Depression and schizophrenia in epilepsy, social and biological risk factors. Epilepsy Res, 35, 59-68.
Smith, D.F., Baker, G.A., Dewey, M., Jacoby, A. and Chadwick, D.W. (1991). Seizure frequency, patient-perceived seizure severity and the psychosocial consequences of intractable epilepsy. Epilepsy Res, 9, 231-41.
Suppes, T., Brown, E.S., McElroy, S.L. et al. (1999). Lamotrigine for the treatment of bipolar disorder, a clinical case series. J Affect Disord, 53, 95-8.
Swann, A.C., Bowden, C.L., Morris, D. et al. (1997). Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry, 54, 37-42.
Trimble, M.R. (1998). New antiepileptic drugs and psychopathology. Neuropsychobiology, 38, 149-51.
Vonck, K., Boon, P., Van Laere, K. et al. (2000). Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy. Epilepsia, 41, 601-9.
Walker, B.R., Easton, A. and Gale, K. (1999). Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia, 40, 1051-7.
Watkins, L.L., Grossman, P., Krishnan, R. and Sherwood, A. (1998). Anxiety and vagal control of heart rate. Psychosom Med, 60, 498-502.
Yeragani, V.K., Pohl, R., Balon, R. et al. (1991). Heart rate variability in patients with major depression. Psychiatry Res, 37, 35-46.
Zabara, J. (1985). Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr Clin Neurophysiol, 61s, S162.
Zabara, J. (1992). Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia, 33, 1005-12.
Zerssen, D.v., Koeller, D.M. and Rey, E.R. (1970). Die befindlichkeits-skala Bf-S - ein einfaches instrument zur objektivierung von befindlichkeits-störungen insbesondere im rahmen von längsschnitt-untersuchungen. Arzneimittelforschung, 20, 915-18.
Zung, W.W.K. (1971). A rating instrument for anxiety disorders. Psychosomatics, 12, 371-9.
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