The present data confirm previous reports that the excitability of short interval intracortical inhibition (SICI) is reduced compared with healthy subjects in patients with either organic or psychogenic dystonia (Espay et al., 2006
;Avanzino et al., 2008
). We also confirmed that short and long latency afferent inhibition are normal in both patient groups (Avanzino et al., 2008
). The novel results concern the paired associative measure of motor cortical plasticity (Stefan et al., 2000
). As reported previously we found that patients with primary dystonia have an increased response to the median nerve PAS protocol, with enhanced facilitation of MEPs in both the median innervated APB muscle as well as the ulnar innervated FDI (Quartarone et al., 2003
;Weise et al., 2006
). In contrast, healthy subjects as well as patients with psychogenic dystonia had normal facilitation in APB and, as expected from the usual topographic organisation of PAS, absent facilitation in FDI. It is unlikely that we underestimated the size of the PAS effect in the psychogenic dystonia group. Indeed they could maintain muscle relaxation in hand muscles, and they attended to the stimuli as well as the patients with primary dystonia. We conclude that patients affected by psychogenic dystonia lack the increased plasticity typical of organic dystonia, even though they share abnormalities of SICI.
There are a number of factors that may have influenced the data from our psychogenic patients. First, only 4 of the patients were clinically definite cases, whereas the other 6 were classified as probable. Although it is impossible to make firm statistical conclusions on the basis of such small numbers, we found no evidence for any differences in the amount of PAS in these two subgroups, suggesting that it is unlikely that our data was contaminated by patients who were wrongly classified. In addition, if the clinically probable patients were to turn out to be healthy normal subjects then we would have expected them to have normal levels of SICI, rather than reduced SICI equal to that in our clinically definite patients (and like that in the clinically definite patients reported by Espay et al (2006)
). A second factor could have been that 4 out of the 10 psychogenic patients were studied on their unaffected side. However, this seems an unlikely explanation of our results since Avanzino and associates (Avanzino et al., 2008
), have previously found abnormal SICI in unaffected body parts of a similar group of patients. A final factor concerns the mechanism of increased PAS in organic dystonia. Although usually ascribed to increased plasticity at cortical synapses, there is a possibility that is results from a steeper input-output slope of TMS intensity v. MEP amplitude compared with control (Rosenkranz et al., 2007
). Thus if this slope is steeper, a PAS facilitation equivalent to increasing the TMS intensity by 10% will increase the MEP amplitude more than in healthy subjects. In the present data we did not plot detailed input-output curves for each group of subjects. However, the absolute MEP threshold and the absolute intensity needed to produce a 1mV MEP was the same in all groups, suggesting that the input-output relations are likely to be very similar.
As noted in the introduction, two main categories of electrophysiological abnormalities have been described in patients with organic dystonia. These are reduced excitability of a number of inhibitory systems in cortex, brainstem and spinal cord (Berardelli, 2006
;Defazio et al., 2007
), and increased responsiveness to probes of synaptic plasticity (Quartarone et al., 2008b
). Reduced inhibition seems unlikely to be a causal factor in organic dystonia since patients with psychogenic dystonia have very similar abnormalities. As suggested by Espay et al (Espay et al., 2006
) and Avanzino et al (Avanzino et al., 2008
), it seems more likely that reduced inhibition may predispose susceptible individuals to develop psychogenic dystonia. In contrast, in organic dystonia, we suspect that reduced SICI may interact with another factor (such as abnormal plasticity) to produce organic dystonia.
Our present data also confirmed that SAI and LAI were the same in organic and psychogenic dystonic patients, and controls (Avanzino et al., 2008
;Espay et al., 2006
). Previous studies suggested that there might be LAI abnormalities in patients with writer's cramp, but not in patients with cervical dystonia (Abbruzzese et al., 2001
;Kessler et al., 2005
). The fact that we studied mixed groups of arm, neck and leg dystonia may explain why we failed to see specific deficits in LAI.
The data confirmed that patients with organic dystonia have an increased response to the excitatory PAS protocol, coupled with a loss of topographical specificity such that increased MEPs are observed in both the median nerve innervated APB muscle as well as the ulnar innervated FDI. In contrast we found that the response to the PAS protocol in psychogenic patients was indistinguishable to healthy controls. We therefore suggest that (a) organic dystonia may require the combination of reduced inhibition (as demonstrated in the SICI data here as well as the additional spinal deficits in reciprocal inhibition noted by Espay et al) (Espay et al., 2006
) plus enhanced plasticity to manifest, whereas (b) reduced inhibition alone might, when combined with other psychological features, predispose individuals to develop psychogenic dystonia.
In animal models, GABAergic inhibitory circuits appear to have an important modulating effect on the induction of long-term potentiation (LTP) at cortical synapses. Indeed, Hess et al (Hess et al., 1996
) found that it was only possible to induce LTP in horizontal connections after reducing GABA transmission with bicuculline. Individuals with psychogenic dystonia have reduced SICI and shorter contralateral silent periods compared to normal (Espay et al., 2006
;Avanzino et al., 2008
), both of which are thought to involve GABAergic connections (GABAA
respectively; see Reis et al., 2008
for review) (Reis et al., 2008
). Thus we might have expected that they would have a tendency towards increased cortical plasticity. However this was not the case. The implication is that not only is the abnormal plasticity seen in organic dystonia unlikely to be secondary to reduced inhibition, but that it may also be a primary causal factor in producing and/or maintaining symptoms.
In conclusion, the findings of the present study confirm that patients with organic dystonia have an increased response to a standard PAS protocol compared with healthy individuals. This may indicate that they have an increased tendency to strengthen sensory-motor associations, perhaps leading to the formation of unwanted muscle contractions and clinical dystonia. This abnormality is not seen in patients with psychogenic dystonia, even though the two conditions share abnormalities in measures of sensorimotor inhibition. We therefore suggest that an increased response to PAS is a hallmark of organic dystonia and that it may be an important contributor to the motor symptoms of the disease.