This study examined 2 neural networks that have been postulated as affected in stuttering. One network involved corticocortical connections linking the articulatory regions within the frontal motor areas and with auditory-sensory areas in temporal–parietal cortex. The other involved the thalamocortical pathway, involving the VLN of the thalamus, which has anatomical connections with motor and premotor cortical regions. The results demonstrated both functional and structural connectivity differences between the stuttering and normally fluent groups in the left inferior frontal to premotor connections, but only functional connectivity differences in the thalamocortical pathway in the stuttering group relative to controls. The functional and structural connectivity results from the corticocortical network are discussed first followed by the thalamocortical results in later sections.
Functional connectivity between the left BA44 and the premotor (BA6) region for both speech and nonspeech oral motor sound production tasks were greater on the left in normally fluent controls but were not seen in stuttering participants. Instead, significantly increased functional connectivity was found between the right BA44 and bilateral speech-relevant cortical regions in the stuttering subjects. These functional connectivity increases with the right BA44 were not seen in controls. The group differences were similar for both speech and nonspeech oral motor sound production.
Structural connectivity measures showed results consistent with the functional connectivity results in the left hemisphere. Major white matter tracts that passed through the same BA44 seed had significantly less tract density in the stuttering participants only in the left premotor and precentral motor regions relative to controls; no group differences in tract density were found on the right side. Hence, both structural and functional connectivity measures supported left-sided group differences, whereas only functional connectivity differences were present for the right hemisphere. These findings underscore previous suggestions of left-sided deficits in stuttering, particularly in the connections between the inferior frontal and the premotor/motor regions (Salmelin et al. 2000
; Sommer et al. 2002
; Neumann et al. 2003
; Neumann et al. 2005
; Chang et al. 2008
A number of recent studies across different research groups have reported attenuated white matter coherence in the left SLF underlying the orolarynx representation of motor cortex for people who stutter both in adulthood and as children (Sommer et al. 2002
; Chang et al. 2008
; Watkins et al. 2008
; Cykowski et al. 2010
). Stuttering adults also differed in the cortical sequence of activity changes involving the left inferior frontal and motor areas during fluent picture naming (i.e., even when they were fluently speaking, the sequence of cortical activity in the left ventral premotor–motor areas were reversed compared with controls) (Salmelin et al. 2000
). A recent study showed that successful remediation of stuttering involved regaining activity in the left inferior frontal region as opposed to engaging the right homologue or adopting other compensatory activity (Kell et al. 2009
). Watkins et al. (2008)
found attenuated white matter coherence as measured with fractional anisotropy and decreased functional activity in the left ventral premotor/inferior frontal region in stuttering speakers (Watkins et al. 2008
). Thus converging evidence point to abnormalities involving the connectivity between the left inferior frontal and the premotor/motor cortex, as areas particularly relevant to the neuropathophysiology of stuttering. The present data suggests, however, that stuttering speakers may exhibit decreased connectivity in motor regions not limited to orolaryngeal representation of the motor cortex. It may be the case that stuttering speakers have less distinction between speech versus adjacent motor representations in the motor cortex. Support for this idea comes from several studies that have reported subtle motor deficits in stuttering speakers not limited to speech movements but also when performing hand and finger movement tasks (Max et al. 2003
; Smits-Bandstra, De Nil, Rochon 2006
There was reduced functional connectivity between the left BA44 and premotor (area 6) regions in stuttering speakers relative to controls, although other functional neuroimaging studies found that stuttering speakers exhibited hyperactivity in the bilateral motor cortices during speech tasks. Further, it was previously found that there were significant correlations between bilateral motor cortex (4p) activity with stuttering severity (Chang et al. 2009
). When the degree of functional connectivity in 4p was examined in relation to BA44 activity during speech/nonspeech production, there was no significant correlation with stuttering severity. This may indicate that left-sided connectivity differences are present in stuttering speakers, regardless of stuttering severity. On the other hand, motor cortex hyperactivity may be present as a reaction to stuttering that appear to be heightened with increasing stuttering severity.
Based on our first hypothesis, evidence of both functional and structural disconnection was expected between BA44 and the left STG in the stuttering group. The lack of functional connectivity differences between BA44 and STG may have been due to the speech and nonspeech tasks that were used. After the subjects were told whether to imitate or reverse the order of the stimuli, they had ample planning (rehearsal time) before producing the speech/nonspeech production. Productions were very short, within a couple of seconds, possibly reducing the need for self-monitoring with auditory feedback during production. To address this issue more directly in the structural analyses, we also conducted a tractography analysis using pSTG seeds to track white matter and measured tract density in the BA44 and motor 4p regions in both hemispheres for these tracts. We found significant tract density differences between the groups only in the left hemisphere in the BA44 but not in motor 4p. This suggests that stuttering subjects may not differ from controls in their ability to send auditory feedback to the motor cortex (4p) for motor adjustment but may still have a disconnection along the tracts flowing between left BA44 and 4p.
When studying adults who have stuttered since childhood it is difficult to determine which differences are part of the initial speech disorder or the result of chronic lifelong attempts to produce speech despite the disorder. The present data offer little support for significant macroscopic structural connectivity differences in the right corticocortical structures between the 2 groups. On the other hand, enhanced functional connectivity in the right hemisphere was demonstrated here and increased right-sided activity has been reported by others (Braun et al. 1997
; De Nil et al. 2000
; Fox et al. 2000
; Chang et al. 2009
). Significant differences in functional connectivity without differences in structural connectivity might suggest that the right hemisphere differences may be the result of, rather than contributors to, the emergence of stuttering symptoms. Heightened right-sided activity during speech tasks (Fox et al. 1996
), and attenuated leftward asymmetry in the planum temporale (Foundas et al. 2001
), have been reported in stuttering adults. In light of the present findings, perhaps these right-sided increases in function may develop as a result of stuttering into adulthood. This is also consistent with the fact that in children who stutter, no right-sided increases and no differences in asymmetry patterns in perisylvian anatomy were found relative to fluent peers (Chang et al. 2008
In regard to the thalamocortical loop, group differences in functional connectivity involving the LVLN included those found in the cerebellum, thalamus, insula, and the STG, which were present regardless of speech or nonspeech tasks. While functional connectivity differences were found in the VLN in both hemispheres, structural connectivity data indicated that the groups did not differ significantly on either side.
The differences found in VLN functional connectivity between the 2 groups suggest that stuttering speakers may differ significantly from controls in how structures within the cerebellum–thalamocortical loop function as a network for volitional speech and nonspeech motor execution tasks. Recently, a similar finding was reported, where using SEM, negative path coefficients were found from the thalamus to the preSMA in controls but positive projections were found from the thalamus to preSMA in the stuttering group (Lu et al. 2010
). In the present data, we did not find significant group differences in the preSMA or SMA but did find differences in regions inferior to these premotor areas, in the cingulate cortex, particularly for speech relative to nonspeech production.
In sum, the present data provide clarifications to previously held suggestions of the neural bases of stuttering that involved deficient corticocortical as well as thalamocortical networks. Of these, we found strongest support for a deficient left inferior frontal to premotor connection in stuttering, as this connectivity was significantly decreased when measured with both functional and structural connectivity analyses. The connections between the VLN thalamus and cortical regions including the premotor and motor areas differed significantly only according to the functional connectivity measures but not structural connectivity.
The functional and structural connectivity differences between stuttering and control groups were not limited to speech production. Nonspeech production that involved similar oral motor structures as used in speech also resulted in very similar patterns of connectivity differences in stuttering speakers relative to controls. Although these connectivity changes were similar for both tasks, some differences were noted. The heightened connectivities on the right side that might be attributed to compensatory connections in stuttering were greater during speech than during nonspeech. For instance, heightened functional connectivity with right BA44 was seen in the motor and cerebellar regions during speech compared with nonspeech in stuttering speakers. These findings underscore the fact that left connectivity differences, which were similar for both speech and nonspeech, may be a trait difference in stuttering, whereas right connectivity differences, found more during speech than in nonspeech, may represent state related differences in stuttering. The convergent finding of attenuated left-sided white matter integrity in stuttering (Sommer et al. 2002
; Chang et al. 2008
; Watkins et al. 2008
) is consistent with a possible disconnection syndrome that may have a genetic basis (Buchel and Watkins 2010
). The recent discovery of mutations of specific genes associated with lysosomal dysfunction which were found in stuttering families (Kang et al. 2010
) might be a neurochemical basis for the white matter deficits, however, much more research is needed to substantiate these claims.
This study has several limitations. We used subject-specific functionally defined seeds in each of the bilateral regions of interest (BA44, VLN) to conduct both PPI analyses and DTI tractography. This procedure, combined with the use of cytoarchitectonically defined maps in the BA44, may have provided a robust estimation of each subject's peak voxel for speech and nonspeech production for this ventral premotor ROI. However, because we did not have cytoarchitectonic maps of the thalamus, we only relied on each subject's functional peak and a less anatomically specific map (Talairach daemon) of the VLN seeds for each individual. This procedure may have led to less accurate anatomical estimation of the peak voxel for these thalamic nuclei. Future studies would benefit from more accurate anatomical localization of the specific thalamic nuclei of interest in each subject. These data are also limited to providing macroscopic differences between the stuttering and fluent speaker groups. There could be microscopic differences (e.g., at the level of lamina, columns, etc.) that we are not detecting due to the nature of the measures used here. Finally, we note that interpretation of functional and effective connectivity differences is tricky and requires caution, especially concerning effects that appear to be compensatory (Kim and Horwitz 2008
). To address this limitation, it might be ideal to track functional and anatomical changes in connectivity measures starting near the onset of stuttering symptoms in children. This may provide a clearer picture of what relates to pathophysiology versus compensatory effects.
In conclusion, we found evidence for both functional and structural connectivity differences in stuttering speakers among the left inferior frontal and premotor cortices. The thalamocortical connectivity differed between the groups only in functional connectivity but not in structural connectivity. The connectivity differences were not only found during speech but also during nonspeech oral motor sound production tasks. Heightened functional connectivity within right hemisphere and interhemispheric cortical regions, as well as between the thalamus and the premotor/motor, cerebellum, and temporoparietal regions were also observed in stuttering speakers but were not corroborated by increased structural connectivity. We propose, based on these results, that the neuropathophysiology of stuttering may involve deficient connectivity among the cortical network of regions that normally allows left-sided engagement of the inferior frontal and premotor cortices for efficient planning and execution of sound production. We also suggest that many previously reported differences involving right hemisphere and subcortical activity in stuttering speakers likely reflect altered functional responses to deficient connectivity of the left premotor/motor areas, although this remains to be determined by studying young children close to symptom onset.