In this report, we highlight the use of multimodality imaging to gain knowledge about speech deterioration following STN-DBS in a single participant with Parkinson’s disease on levodopa medication. Unique in this report is the combination of objective measures of speech (perceptual and acoustic) with PET imaging and “virtual lesion” techniques to understand the underlying neural mechanisms responsible for speech impairment due to DBS.
Similar to previous studies (e.g. Pinto, Ozsancak, et al., 2004
), speech was found to deteriorate with stimulation to the left STN in this patient. The use of Darley et al.’s (1975)
multidimensional rating system in this study provided greater specificity to the nature of the speech impairment than that has been previously reported, revealing deficits characteristic of hypokinetic dysarthria in Parkinson’s disease (e.g. short phrases, monopitch, monoloud, imprecise consonants, intelligibility) as well as others that are not typically found in individuals with Parkinson’s disease (harsh, strained/ strangled vocal quality). Multidimensional perceptual ratings may provide clues to the nature of the mechanism underlying speech deterioration sometimes found in Parkinson’s disease patients with STN-DBS. For example, harsh and strained/strangled vocal qualities typically are associated with spastic dysarthria. These perceptual findings suggest that STN-DBS in this patient is stimulating not only the subthalamic nucleus and connected basal ganglia, but may be inadvertently stimulating fibers in the corticospinal tract as well ().
Figure 7 Schematic representation of effects of STN-DBS in Parkinson’s disease. Orange lines represent excitatory connections and grey and black lines represent inhibitory connections. Direct and indirect stimulation of STN by DBS is indicated by box with (more ...)
Speech changes associated with STN-DBS were assessed with acoustic measures previously used in speakers with hypokinetic dysarthria due to Parkinson’s disease (Rosen et al., 2006
). These measures provided evidence of STN effects on speech, resulting in blurred acoustic boundaries (pause percentage time), reduced differentiation between consonant and vowel sounds (spectral range), and decreased acoustic contrastivity (i.e. variation in the intensity envelope, important for normal prosody). In contrast, with DBS off or on only to the right side, acoustic contrastivity measures were more similar to reported data from speakers with Parkinson’s disease and hypokinetic dysarthria (Rosen et al.). Overall, this pattern of acoustic results indicates a loss of acoustic contrastivity when DBS was applied to the left STN, while absence of stimulation or stimulation to the right STN resulted in a higher degree of contrast. Similar differential effects of left and right DBS on speech has been previously reported (Wang et al., 2003
), where the intensity of maximally sustained vowel phonation was shown to be improved only during right DBS on when compared to both baseline and left DBS on.
Furthermore, it might be expected that spectral contrast measures during DBS off and TMS off should be more similar than found (). However, IV, PPT, and SR for TMS off did not vary appreciably compared to TMS on, and were generally more comparable with the DBS on conditions. This pattern of effects may indicate that the disrupted articulatory plans generated in left PMd during TMS on were carried out by the motor cortex during TMS off and resulting in a “spillover” of TMS-induced disruption into the TMS off period.
The speech-related functional activation patterns for reading contrasted with rest (DBS on and off) found in this participant are similar to the previously reported pattern in Parkinson’s disease (Liotti et al., 2003
; Narayana et al., in review
; Pinto, Thobois, et al., 2004
). Local and remote increases in CBF with DBS on that were found in this participant are also consistent with published literature (Haslinger, Kalteis, Boecker, Alesch, & Ceballos-Baumann, 2005
; Hershey et al., 2003
). Unilateral activity at the site of stimulation even when both stimulators are on as seen in this participant has been reported in other STN-DBS studies (Asanuma et al., 2006
; Hershey et al.). Further, decreases in CBF seen in the primary motor cortex (M1), and the supplementary motor areas (SMA) following STN stimulation with DBS is consistent with the published literature (Haslinger et al.; Hershey et al.). These studies also report decreased CBF in left PMd when DBS is on. The neural mechanism of these CBF changes is not well characterized. However, we found that the DBS on vs. off contrast revealed an unexpected area of hyperactivation in the left PMd (see ). Therefore, we investigated the role of left PMd in speech production and whether the abnormal activation of this region could explain the speech disorder in this participant.
Various functional studies also have shown activation of PMd in normal speech (Bookheimer, Zeffiro, Blaxton, Gaillard, & Theodore, 2000
; Petersen, Fox, Posner, Mintun, & Raichle, 1988
; Price, Moore, & Frackowiak, 1996
; Schulz, Varga, Jeffires, Ludlow & Braun, 2005
; Watkins, Gadian, & Vargha-Khadem, 1999
; Wise et al., 1991
; Wise, Greene, Büchel, & Scott, 1999
), as well as in motor speech disorders such as stuttering (Brown et al., 2005
) and Parkinson’s disease (Narayana et al., in review
). Several lesion studies indicate that PMd is important in speech programming (Fox et al., 2001
; Robin, Jacks, & Ramage, 2008; Watkins, Dronkers, & Vargha-Khadem, 2002
), phonemic speech production (Larner et al., 2004
), and phonetic perceptual processing (Demonet et al., 1992
; Zatorre, Evans, Meyer, & Gjedde, 1992
; Zatorre, Myer, Gjedde, & Evans, 1996
). Previous work in our center has also shown that TMS stimulation to this area disrupts speech in healthy, unimpaired speakers (Robin, Guenther, et al., 2008; Tandon et al., 2003
). The role of PMd in normal speech production is thought to involve working memory storage of units/programs for speech production (Mass et al., 2008; Robin et al., 2007, Wright et al., in press). The increased blood flow in PMd during normal speech therefore can be thought to be a result of neurons firing in a temporal hierarchical and a synchronous pattern. However during DBS-on the neurons in left PMd are stimulated continuously also resulting in an increased blood flow. Functional imaging method such as PET do not have the temporal resolution to differentiate the timing of cortical processes involved in speech that usually occur in milliseconds. Therefore in PET, neuronal firing during normal speech (i.e. periodic firing of neurons) and DBS-on (i.e. continuous firing of neurons) neuronal firing appears as activations. Further, continuous stimulation or ‘out of phase’ firing resulting from direct antidromic stimulation from DBS (or TMS) and the resulting de-synchronization of ongoing activity, disrupts the normal function of left PMd. Therefore speech disruption seen during DBS as well as TMS are a direct result of de-synchronization of ongoing activity in the left PMd. Verification of left PMd as critical to the worsening of speech in this patient was obtained with irTMS when the stimulators were turned off. As noted, stimulation of this area in this patient produced a speech deficit that was perceptually similar to that found with STNDBS.
It is not well understood how STN-DBS increases CBF in PMd. Recently, using MR tractography, connections have been shown between STN and several cortical areas such as PMd, SMA, M1-hand, M1-trunk and M1-fore upper limb (Aravamuthan et al., 2007
). An upstream antidromic (i.e. propagation of action potential from the axon to the cell body) modulating effect of STN stimulation on these direct cortico-subthalamic projections has been proposed (Haslinger et al., 2005
). High frequency stimulation within the STN has been shown to induce negative frontal cortical potentials, further supporting the direct antidromic stimulation of cortico-subthalamic axons (Ashby et al., 2001
). Therefore, one potential explanation of this finding is that bilateral or left-sided stimulation of STN in this participant resulted in antidromic activation of left PMd, thereby causing speech to deteriorate with STN-DBS. This is depicted in . Stimulation of STN by DBS results in orthodromic (i.e., the propagation of action potential from cell body to the axon) disruption of excitatory effect of STN on the internal segment of globus pallidus (GPi). The net outcome of this disruption is the release of inhibition on the thalamus and motor cortex and improvement in limb motor symptoms of Parkinson’s disease. However, at the same time, stimulation of STN can propagate in the antidromic direction along the cortico-subthalamic fibers and could result in speech impairment.
The notion of Farrell and colleagues (Farrell et al., 2005
) that speech motor planning/programming may be disrupted as a result of STN-DBS is in line with our findings, as stimulation of PMd only disrupts speech attempts and not silent reading (Tandon et al., 2003
). Thus, we hypothesize that DBS disrupts ongoing processes in left PMd (for example during speech) by adding noise to the system vis-à-vis antidromic stimulation. Virtual lesioning by TMS also resulted in such disruption of ongoing activity in left PMd during overt speech. This finding points to the role of PMd in speech motor programming. Furthermore, DBS could result in speech deficit not only by direct disruption of PMd activity, but also indirectly by interfering with the interactions between PMd and the primary motor cortex. Excitability of PMd has been shown to directly modulate the primary motor cortex (Reis et al., 2008
As noted in the introduction, explanations for the differential responses to stimulation observed for speech versus general motor behavior are speculative, ranging from hypotheses about electrode placement to differential neural organization of speech and limb motor systems. Relative to electrode placement, appropriate increases in CBF in STN, thalamus and basal ganglia were demonstrated bilaterally using PET imaging with DBS on (). Further, improvement in limb motor performance when DBS was on indicates appropriate positioning of electrodes. However, the exact site of stimulation in this patient is not known as post-operative MRI was not performed.
Topographically, there is evidence that the STN regions connected to the cortex (i.e. motor cortex, SMA and PMd) are located in close proximity and are more lateral and anterior to the STN regions connected to other brain regions (i.e. basal ganglia and thalamus; Aravamuthan et al., 2007
). Therefore, DBS can directly stimulate areas in STN connected to the premotor cortices as well as the primary hand, trunk and upper limb motor areas. In the superior-inferior dimension (z plane) STN regions connected to PMd and SMA were segregated from those parts of STN connected to the motor cortex (Aravamuthan et al.). Thus, even a small displacement of the DBS in the z direction can stimulate not only regions in STN connected to the primary motor cortex but also areas of STN connected to SMA and PMd. Therefore, while improving motor function by lesioning the connections of STN to the motor cortex, DBS might incidentally lesion its connections to the premotor areas. This can also explain the speech disturbances found in our participant with Parkinson’s disease and STN-DBS. Such differences in the location of the implanted electrodes can explain why some patients with DBS do have speech problems.
Farrell and colleagues (2005)
have argued that disruption of speech due to STN-DBS results from activation differences in local neuronal population responses and fundamental differences in their role in the regulation of speech and limb movements. The argument that speech planning and execution are driven by different neural organization schemes than other motor systems has been challenged in the literature, particularly for high-level motor organization and programming (Ballard, Robin, & Folkins, 2003
). Another point made by Farrell et al. is that limb systems receive unilateral (contralateral) innervation via corticospinal inputs whereas speech structures, which project to corticobulbar systems, include bilateral innervation patterns of some muscle groups. It is unclear how these differences in innervation patterns would lead to poorer or no response of speech to DBS in the face of positive limb responses, particularly given our finding that right-sided stimulation has minimal or no detrimental effects on speech. Our findings support similar findings by others (Wang et al., 2003
) and their argument about motor asymmetry.
In summary, one patient with long-standing Parkinson’s disease who was implanted bilaterally with STN-DBS was studied. Unique in this report was the combination of objective measures of speech (perceptual and acoustic) with PET and MRI imaging as well as “virtual lesion” methods using TMS to understand the underlying neural mechanisms responsible for speech impairment due to DBS. Although these data are based on only one patient, they provide a strong direction for future research efforts. We have provided preliminary evidence to explain the neural mechanism underlying speech deterioration in patients with Parkinson’s disease and STN-DBS. The finding that right-sided stimulation resulted in speech that was in many ways perceptually better than when the stimulators were off, might allow for balancing the intensity of stimulation between hemispheres as a successful treatment strategy. If these findings hold for other patients with STN-DBS, then image-guided adjustment of STN-DBS parameters may promote improvement in ALL motor functions.