Despite the beneficial effects of STN DBS on the motor symptoms of PD, the effects on cognition are highly variable. The present study demonstrates that STN DBS-induced change in WM performance is associated with change in regional blood flow in the DLPFC, while change in RI task performance is associated with change in regional blood flow in the ACC. These correlations were specific and as predicted. In fact, the exploratory ROI analyses provide converging evidence and further support the specificity of these relationships. The results are consistent with frontal-striatal circuitry and the neurophysiological effects of STN DBS as well as the functional role of these areas in cognitive control. These relationships were not due to participant characteristics such as age, motor symptom severity, or motor benefit from STN DBS. In addition, the results indicate an inverse relationship between regional blood flow and cognitive control as measured by both tasks; STN DBS-induced increases in regional blood flow were associated with decreased cognitive control, whereas STN DBS-induced decreases in regional blood flow were associated with increased cognitive control performance. However, the factor(s) contributing to the variability in responses to STN stimulation, which may mediate the relationship between blood flow changes and cognitive control, are yet to be determined.
The key finding of the present study is that the stimulation-induced change in cognitive control performance was inversely related to the stimulation-induced change in regional blood flow in the DLPFC and ACC. Importantly, the relationship between cognitive control and regional blood flow changes was not limited to just the degree of change, but also the direction. Participants with stimulation-induced decline in cognitive control performance demonstrated stimulation-induced increased blood flow in the relevant cortical regions whereas participants with improved cognitive control performance had reduced rCBF in these same regions (see ). The specific relationships between blood flow change in the DLPFC with WM and blood flow change in ACC with RI performance further support the notion that these areas are important for cognitive control (Braver et al., 2001
; Leung et al., 2002
Despite the evidence from other studies demonstrating that rIFC is involved in response inhibition, our exploratory analysis of DBS-induced blood flow responses in this area did not indicate any relationship with stimulation-induced changes in GNG performance. Similarly, stimulation induced blood flow changes in the majority of the exploratory ROIs from the meta-analyses were not related to stimulation-induced changes in cognitive performance. Several possible reasons may explain these negative finding. First, methodological differences may account for our seemingly discrepant findings. For example, the majority of the research demonstrating involvement of the rIFC in response inhibition has utilized the Stop Signal Task (c.f., Aron & Poldrack, 2006
), which requires the inhibition of an already initiated response, whereas the GNG task in the present study requires the inhibition of a prepotent (but not yet initiated) response. In fact, there is even evidence for differences in cortical activation based on the specific GNG task that is used (Simmonds, Pekar, & Mostofsky, 2008
). A second possibility may relate to individual or group differences. The participants in the current study were primarily older adults, who may rely on slightly different functional neuroanatomy for response inhibition and working memory (c.f., Jennings, van der Veen, & Meltzer, 2006
; Nielson, Langenecker, & Garavan, 2002
). Finally, and most likely, it is highly probable that the rIFC and other areas are involved in response inhibition and working memory, but that they do not mediate the stimulation-induced changes in cognitive performance. The DLPFC and ACC, however, are specific targets of frontal-striatal circuits (Alexander et al., 1990
; Alexander et al., 1986
; Middleton et al., 2000
), demonstrate altered rCBF with STN stimulation (Sestini et al., 2002
), and are also involved in WM and RI performance.
Several caveats regarding this study should be noted. Our main findings are based upon correlational analyses and do not prove causal relationships between the STN DBS-induced changes in blood flow and cognitive control performance. However, this type of analysis does provide meaningful information. If the STN DBS-induced behavioral change depends on functional modifications of basal ganglia-prefrontal circuits that can be measured by cortical blood flow changes, then these changes should be correlated. Our findings support this interpretation and are consistent with a potential causal relationship. Although we failed to confirm a significant STN DBS-induced impairment of cognitive control, these results fit with the high degree of variability in cognitive and blood flow responses to STN DBS across studies (Burn & Troster, 2004
; Takeshita et al., 2005
; Temel et al., 2005
; Voon et al., 2006
),. In this study, the mean change in cognitive response to STN stimulation was in the direction of impairment but did not reach statistical significance due to the high variability across participants. In fact, this variability across participants permitted us to identify significant correlations between changes in behavioral performance and blood flow response to STN DBS. The factors driving these differing individual responses have not yet been identified nor have their mechanisms of action been delineated, thus requiring further investigation.
A change in blood flow could reflect alterations in interneuronal activity within these regions (DLPFC or ACC), changes in input from distant pathways such as the basal ganglia-thalamo-cortical circuits, or both, since regional blood flow changes reflect neuronal activity in target synaptic fields. Therefore, measurements of stimulation-induced blood flow changes permit insight into possible underlying mechanisms (Hershey & Mink, 2006
). Some have hypothesized that STN DBS forces “regularization” of irregular STN output leading to improved motor performance in people with PD (Vitek, 2002
). Although regularization of STN output may improve motor function, a forced regular rate of firing may interfere with the phasic burst firing related to cognitive control processes (Funahashi et al., 1989
; Kropotov & Etlinger, 1999
; Schultz, 1997
). Our findings support this idea. Stimulation-induced increased input or interneuronal activity in DLPFC or ACC could override the firing patterns that support optimal cognitive control functioning. Likewise, reduced input or interneuronal activity in these prefrontal regions could reflect decreased competition or noise thereby permitting firing patterns underlying cognitive function to operate more optimally. The crucial next step is to identify the factor(s) that determine the neurophysiological response to STN DBS as this may also mediate the cognitive response to STN stimulation.
It is possible that stimulation variables, such as the precise location of the active electrode contact, the extent of the field of stimulation (Morrison et al., 2004b
; Smeding et al., 2007
; Temel et al., 2006
) or patient variables, such as degree of dopaminergic denervation (Foster, Black, Antenor-Dorsey, Perlmutter, & Hershey, 2007
; Hershey et al., 2007
) could modulate cognitive control as well as the direction and degree of change in associated prefrontal cortical blood flow. For example, without direct visual identification of electrode contacts within the brain, uncertainty remains regarding their precise location and the spatial extent of the effects of stimulation, both of which may contribute to STN DBS effects (Temel et al., 2005
). The frequency, voltage, and amplitude of STN stimulation also could influence cortical functioning (Strafella et al., 2003
; Temel et al., 2005
). Future studies that incorporate the exact location of contacts as well as stimulation variables, including the degree and strength of current spread, may be useful in understanding the physiological characteristics of the anatomical pathways underlying the cognitive effects of stimulation.