study: A "sticky" interhemispheric switch in bipolar disorder?
This seems to be an interesting/useful study about the left and right brain not cooperating in people with bipolar. I am posting it here because I don't know where else.
This research shows that people with bipolar have a delay in switching brain hemispheres.
Click on the link to see graphs and diagrams.
This is the study that suggests that cold caloric stimulation of the left ear (activating the right hemisphere) might temporarily reduce the symptoms of mania, while depression might be temporarily reduced by cold right ear caloric stimulation.
:icon_arrow: very cold water in left ear can temporarily reduce manic symptoms
:icon_arrow: very cold water in right ear can temporarily reduce depressive symptoms
A "sticky" interhemispheric switch in bipolar disorder?
JOHN D. PETTIGREW AND STEVEN M. MILLER
Vision, Touch and Hearing Research Centre, University of Queensland, St Lucia, Brisbane, 4072, Australia
http://www.uq.edu.au/nuq/jack/procroysoc.html
Quote:
SUMMARY
Despite years of research into bipolar disorder (manic depression), its underlying pathophysiology remains elusive. It is widely acknowledged that the disorder is strongly heritable but the genetics are complex with less than full concordance in monozygotic twins and at least four susceptibility loci identified.
We propose that bipolar disorder is the result of a genetic propensity for slow interhemispheric switching mechanisms that become "stuck" in one or the other state.
Since slow switches are also "sticky" when compared with fast switches, the clinical manifestations of bipolar disorder may be explained by hemispheric activation being "stuck" on the left (mania) or on the right (depression). Support for this "sticky" interhemispheric switching hypothesis stems from our recent observation that the rate of perceptual alternation in binocular rivalry is slow in euthymic subjects with bipolar disorder (n=18, median=0.27Hz) compared with normal controls (n=49, median=0.60Hz, p<0.0005).
We have have presented evidence elsewhere that binocular rivalry is itself an interhemispheric switching phenomenon. The rivalry alternation rate (putative interhemispheric switch rate) is robust in a given individual, with a test-retest corrrelation of >0.8, making it suitable for genetic studies. The interhemispheric switch rate may provide a trait-dependent biological marker for bipolar disorder........
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4. DISCUSSION
(a) Genetics
.......Interhemispheric switching in binocular rivalry may be mediated by bistable oscillator neurones located in the brainstem. While the switch is likely to have top-down influences, the fundamental rhythm may be determined intrinsically, as for other bistable oscillators, by the number of cationic currents that drive the rate of depolarization (Fig. 5). The rate would be directly proportional to the number of channels present (Rowat & Selverston 1997; Marder 1998). If the slowed rivalry rate that we have observed in bipolar patients proves to be a reliable trait marker for the disorder, we would predict that the relevant genes would be associated with some of the many cationic channels that have been described so far. There are multiple different cationic channels, each of which might contribute to the rhythm of the switch, such as the family of hyperpolarisation-activated channels (Gauss et al. 1998, Ludwig et al. 1998). This functional multiplicity could explain the well recognized failure of linkage studies to settle on a single chromosomal locus (e.g. Adams et al. 1998; McGue & Bouchard 1998). We are currently assessing the slow rivalry trait in family studies to assess its pattern of inheritance, and in twin studies to look at heritability. A quantitative trait such as this may be more revealing in genetic studies than the more limited, qualitative information available from the presence or absence of clinical episodes.
(b) A Model of Bipolar Disorder
Slow switches are "sticky" switches because the intrinsic channel abnormalites causing slow oscillation rate, also make the switch more likely to be held down in one state by external synaptic inputs (Rowat & Selverston 1997). At first sight, there is a conflict between our suggestion that the primary defect is a reduction in cationic channels and the many findings of increased cellular and neuronal sensitivity in bipolar disorder, since cationic channel reduction would have the general effect of decreased neuronal sensitivity.
Documented examples of increased neuronal sensitivity in bipolar disorder include:- 1. elevated levels of G proteins (Mitchell et al. 1997; 2. increased responsiveness of cAMP processes (Andreopoulos et al. 1997); 3. Increased sensitivity to light-induced melatonin suppression (Nurnberger et al. 1988); 4. Increased sensitivity to cholinergic REM sleep induction (Nurnberger et al. 1983).
We suggest that these apparent contradictions can be resolved if the primary effect on the timing of the oscillator is distinguished from the "downstream" effects on other parts of the brain, such as the cerebral hemispheres, where compensatory mechanisms may be employed to restore normal levels of excitability in the face of reduced cationic channel function. For example, the cerebral hemispheres may be concerned more with neuronal excitability and plasticity than with clock rate. Since many effective medications for bipolar disorder (e.g. lithium) are known to decrease excitability via G-protein and cAMP mediated processes, we suggest that their mechanism of action may be upon these downstream effects rather than on the defect in the oscillator per se.
Since the cerebral hemispheres provide an important "top-down" synaptic input to the brainstem switch, a compensatory increase in sensitivity would lead to increased hemispheric output (in response to a stressor) and might therefore increase the likelihood that the switch will be held down ("stuck") on the side favouring that hemisphere.
The switching process in bipolar patients might therefore be doubly afflicted; increased "stickiness" because of reduced intrinsic currents and potentially greater extrinsic synaptic inputs from stressors by virtue of the compensatory increase in hemispheric excitability.
We therefore envisage a manic or depressive episode being the result of a stressor that causes the switch to be "stuck" in one of two positions:- unrelieved left hemisphere activation being associated with mania, in line with that hemisphere's cognitive style, unrelieved right hemisphere activation being associated with depression, in line with its style.
(c) Hemispheric Asymmetries of Mood and Mood Disorder
Hemispheric asymmetries of mood and mood disorder have been widely discussed (Kinsbourne (ed) 1988; Davidson & Hugdahl (eds) 1995; Heller & Nitschke 1997). Imaging studies suggest that there is greater relative right prefrontal activation in depression - i.e. left prefrontal 'hypometabolism' - which was not present when subjects were rescanned following clinical remission (Bench et al. 1995; Martinot et al. 1990).
EEG studies also support greater relative right activation in depression (Henriques & Davidson 1991). Activation asymmetries favouring the left hemisphere have been reported in mania (Migliorelli et al. 1993). In keeping with these activation asymmetries, it has been shown that transcranial magnetic stimulation of prefrontal cortex is therapeutic for depression when administered on the left (George et al. 1997; Pascual-Leone et al. 1996).
Unilateral hemisphere inactivation using sodium amobarbitol has also been associated with asymmetric mood sequelae.
Inactivation of the left hemisphere has been shown to induce negative moods more commonly on subjective measures (Christianson et al. 1993) while objective measures of affect showed crying to be related to left hemisphere injections and laughter/elation to right-sided injections (Lee et al. 1990). Lesion studies have been particularly illuminating with respect to asymmetries.
Robinson and Downhill (1995) report that left-sided lesions in prefrontal and basal ganglia regions are more commonly associated with depression than similar lesions on the right, and secondary mania more commonly follows right-sided lesions (basotemporal cortex, orbitofrontal cortex, basal ganglia, thalamus) than similar left-sided lesions.
Robinson and Downhill (1995) suggest that the dependence of mood change on lesion site may be the result of asymmetric pathophysiologic responses to injury. While such mechanisms may be relevant, studies of emotion and mood in normal subjects (Davidson, 1995) support the notion of underlying physiological asymmetries which would also explain the lesion data. This interpretation does not exclude asymmetric response to injury since asymmetries of physiologic function may be mediated by neurochemical asymmetries.
Thus a wide variety of data suggests that there are hemispheric asymmetries of mood and mood disorders.
There are, of course, methodological limitations and several studies have been unable to replicate reported asymmetries. It is not pertinent to review such issues in this paper. Taken alone, each approach (psychiatry, neurology, neuropsychology) may be criticized. Taken together, the directional convergence of results from disparate modes of investigating asymmetries of mood and mood disorder seems unlikely to be due solely to issues of methodology or interpretation.
(d) Slowed Oscillator for Frontal and Limbic Regions?
The notion of alternating hemispheric activation has been suggested before and is supported by electrophysiological and psychological studies of ultradian rhythms (<20 hrs duration) of cerebral dominance (for a review see Shannahoff-Khalsa 1993).
The typical period for such rhythms is in the minutes to hours range. The oscillator for binocular rivalry targets regions at high stages of visual processing in temporo-parietal cortex, based on neurophysiological evidence from monkeys undergoing rivalry (Sheinberg & Logothetis 1997), and on magnetic resonance imaging studies of humans (Lumer et al. 1998). An interhemispheric switch for cognitive style and mood would be likely to engage frontal and limbic regions (Liotti & Tucker 1995) and to have a period similar to that of reported ultradian rhythms of cerebral dominance (i.e. minutes to hours). A slowing of the oscillator for rivalry, from 1-2 seconds to 10-20 seconds, would not account for any of the clinical phenomenology of bipolar disorder. It is conjecture on our part to propose that the slowing of an oscillator for temporo-parietal cortex might also be accompanied by a proportionate slowing of the putative oscillators that govern interhemispheric switching in other regions such as prefrontal cortex. There is a precedent for such coupling in Drosophila where a single mutation may simultaneously reduce the rate of both short period (ultradian) and longer period (circadian) oscillators (Hall & Rosbash 1988; Kyriacou and Hall 1980). The question of coupled oscillators is clearly relevant to mood disorders such as seasonal affective disorder (Teicher et al. 1997; Madden et al. 1996; Corbera 1995) and to the way in which cortical regions activated by different rates might be coupled by virtue of their pooled outputs to the same switch (Pöppel et al 1978).
(e) Clinical effects of caloric stimulation in bipolar disorder?
In view of the efficacy of caloric stimulation in inducing unilateral hemispheric activation (Bottini et al. 1994; Vitte et al. 1996), we suggest that caloric stimulation in acutely manic or depressed patients might support our model of bipolar disorder. The technique is known to temporarily reverse unilateral neglect and anosognosia associated with right-sided lesions (Cappa et al. 1987; Vallar et al. 1993; Ramachandran 1994).
Thus cold caloric stimulation of the left ear (activating the right hemisphere) might temporarily reduce the symptoms of mania, while depression might be temporarily reduced by cold right ear caloric stimulation.
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