This study directly manipulates stimulation across the dorsolateral/ventromedial dimension of the STN region in a controlled, double-blind and within-subjects design. Results indicate that stimulation of the ventral, but not dorsal, STN region impairs cue-driven behaviour of a prepotent motor response, while stimulation of both STN regions improves Parkinson’s disease motor sign ratings. The dissociation between location of stimulation and responses across two functional domains (motor and cognitive) may reflect a difference in the dispersion of motor versus cognitive circuits through the STN region. Whereas motor function may be widely dispersed across the dorsolateral/ventromedial dimension of the STN, cognitive functions underlying performance on tasks such as Go–No-Go may be more restricted to the ventral STN region. These findings are consistent with clinical reports suggesting that STN DBS has robust effects on the motor signs of Parkinson’s disease but that cognitive responses to STN DBS are more variable.
As we and others have found, DBS STN affects task conditions with higher cognitive control demands, including but not limited to Go–No-Go. These tasks include noun/verb generation (Castner et al., 2007
), declarative recall (Halbig et al., 2004
) and verbal associative fluency (Rothlind et al., 2007
). In contrast, STN DBS can improve performance on extinction (Funkiewiez et al., 2004
) and non-declarative memory tasks (Halbig et al., 2004
). This pattern suggests that tasks with greater cognitive control demands are most susceptible to the negative effects of STN DBS. In this context, our data do not necessarily support task specificity of the effects of DBS STN; rather these data strongly suggest location specificity of the effects of STN DBS on Go–No-Go performance, which could be a sign of a more fundamental change in higher order attentional control. Finally, this study may have clinical implications for the consideration of contact location within the STN region for optimal non-motor outcome.
This study has a number of important and unique strengths. We performed within-subject comparisons using fixed stimulation variables, altering only location of the contact used to deliver current. In contrast, previous STN DBS studies have tended to use clinically determined stimulation settings, which can vary substantially in the current applied, location of active contact within the STN and even the contact configuration used (e.g. monopolar versus bipolar). The experimental design in our study reduces between-subject variability in clinical characteristics or stimulation parameters. In addition, participants were tested in the ‘practically defined off’ medication state, reducing variability across individuals and potential interactions between medication and stimulation effects on response inhibition. Given the reported direct effects of dopaminergic medication on response inhibition (Cools et al., 2003
; Frank et al., 2007
), reducing this potential confound when testing the effects of DBS is important. Although changes in overall motor function and speed/accuracy trade-offs across stimulation conditions could explain changes in cognitive task performance, our results are not consistent with such explanations. Indeed, in our study, motor and cognitive responses were dissociated across stimulation conditions: both stimulation conditions improved motor performance, neither condition changed Go–No-Go reaction time and only ventral stimulation impaired Go–No-Go accuracy. Finally, we used a validated and reliable method for identifying the location of contacts within the STN region. We did not rely on surgical targeting data, which may not precisely correlate with the final position of the contacts, or on visual inspection of post-surgical MRIs that might contain artefacts induced by the DBS lead and that poorly define the boundaries of the STN (Dormont et al., 2004
). Instead, we used a validated atlas registration method tailored to derive an objective and quantifiable fit in the STN region.
Limitations of this study include the relatively small sample size and unilateral stimulation conditions, which make strong tests of any hemispheric asymmetry of response inhibition mediation difficult. Although the role of the right STN and right inferior frontal gyrus in response inhibition has been emphasized (Aron et al., 2004
), the literature does not consistently support this idea (Ray et al., 2009
). Further, previous work on a large sample comparing left and right unilateral STN DBS on Go–No-Go performance found that stimulation on the more affected side of brain had the greatest impact on performance, not hemisphere of the brain (Hershey et al., 2008
). On a related note, we had to vary which hand was used to respond in the Go–No-Go task across participants. However, after thoroughly exploring this potential confound, we conclude that it is highly unlikely that any differences in hand used explain our primary results.
In terms of clinical relevance, our study does not imply that the motor benefit from dorsal and ventral STN DBS is equal or that there is no ‘sweet spot’ with respect to optimal DBS-induced motor benefit. We purposefully used a low DBS voltage (2.5
V) in our study, based on clinical observation that a higher DBS voltage applied close to the internal capsule or substantia nigra is likely to cause adverse effects. However, a higher voltage could reveal that dorsal DBS provides a more substantial motor benefit than ventral DBS or that our motor effects are underestimates of what is present in the clinical setting. Finally, we recognize that DBS current spread probably affects fibres of passage and structures near the dorsal STN, such as the zona incerta and structures near the ventral STN, such as the substantia nigra pars reticulata. We cannot exclude the contributions of these regions or pathways to the behavioural effects seen with STN DBS in clinical settings, other STN DBS studies or in our study. Nevertheless, we clearly distinguished effects from stimulation in the region of dorsal STN from stimulation of the region of ventral STN; estimated current spread between these two regions was clearly spatially different and is probably more constrained in our study than with typical clinical settings.
Our findings have a number of important implications for models of neural systems underlying response selection and inhibition. Aron et al.
(Aron et al., 2004
; Aron and Poldrack, 2006
) have posited that the STN is involved only when there is an ongoing response that has to be stopped mid-stream (as in the stop signal task) but not when inhibition of a prepotent (but not yet initiated) response is needed (as in Go–No-Go). They base this distinction in part on a study that did not find an effect of STN DBS on a Go–No-Go task (van den Wildenberg et al., 2006
). However, that study was conducted while patients were on dopaminergic medications and used clinically chosen DBS contacts and stimulation settings. More recent papers and the current study suggest that this distinction between tasks should be softened and support a more general role of the STN in response discriminability in high conflict situations (Aron et al., 2007
). For example, a recent study showed that STN DBS induced faster and less accurate responses in high conflict win-win decision trials on a probabilistic selection task (Frank et al., 2007
). The authors hypothesize that the STN sends a ‘No-Go’ signal to the internal segment of the globus pallidus, which ultimately raises decision thresholds in the face of conflict. Stimulation may disrupt this signal, leading to inappropriately unchanged or even lowered thresholds in conflict situations. Our results here indicate that the ventral STN but not the dorsal STN region plays a role in this process and may be involved in both aspects of cue-driven behaviour, engaging and inhibiting the correct motor response in conflict situations.
These findings have broader implications for the proposed functional map of the STN. Previous proposals have emphasized the distinct regions of the STN based on anatomical work: motor circuits in the dorsal and lateral STN, cognitive circuits in the ventral and medial STN. However, our data suggest that motor function can be positively influenced by stimulation along the dorsolateral/ventromedial axis of the STN. This finding is consistent with evidence that in optimally treated patients there is significant variability of the location of the clinically chosen contact (Saint-Cyr et al., 2002
; Starr et al., 2002
; Mallet et al., 2007
; McClelland, III et al., 2007
). In summary, our study highlights the need to be cautious in treating DBS as an anatomically and functionally uniform challenge to the STN. Our findings are also consistent with the idea that different functional pathways involving the STN (e.g. motor and cognitive) may not be tightly segregated, but rather interspersed to some degree at the level of the STN (Mallet et al., 2007
) or downstream (Haber et al., 2000
; McFarland and Haber, 2000
In addition, previous maps of the STN have been two-dimensional, focusing on the dorsal–ventral dimension through the anterior–posterior centre of the STN, where it is largest. However, the shape of the STN tapers dramatically anterior and posterior to this central portion, and it is unclear how functions are mapped throughout this dimension. It is important to note that in our data, due to the trajectory of the implanted electrode, the position of the dorsal and ventral contacts differs as expected in the dorsal–ventral dimension (z), but also the anterior–posterior dimension (y). To build a three-dimensional map of the STN, greater sampling of contact locations across all dimensions of the STN with concurrent measurements of all behavioural domains (motor, cognitive and mood) would be necessary.
Finally, understanding the stimulation variables, such as contact location, that influence cognitive function in patients with STN DBS may help to devise better programming strategies. We could then minimize the risk for cognitive impairment while maximizing the benefit for motor function depending on the stimulation settings chosen. In the future, it may be possible to assay the cognitive skills that are most sensitive to STN DBS during programming, guiding the programmer to choose the contact that provides the least adverse cognitive effects while still providing acceptable motor benefit.