Paired inhibitory stimulation and gait training modulates supplemental motor area connectivity in freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD). Evidence suggests patients with FOG have increased cortical control of gait. The supplementary motor area (SMA) may be a key structure due to its connectivity with locomotor and cognitive networks. The objectives of this study were to determine (1) if SMA connectivity is disrupted in patients with FOG and (2) if "inhibitory" repetitive transcranial magnetic stimulation can decrease maladaptive SMA connectivity. METHODS: Two experiments were performed. In experiment 1 resting-state (T2* BOLD imaging) was compared between 38 PD freezers and 17 PD controls. In experiment 2, twenty PD patients with FOG were randomized to either 10 sessions of real or sham rTMS to the SMA (1 Hz, 110% motor threshold, 1200 pulses/session) combined with daily gait training. RESULTS: (Experiment 1) Freezers had increased connectivity between the left SMA and the vermis of the cerebellum and decreased connectivity between the SMA and the orbitofrontal cortex (pFDR-corr <0.05). (Experiment 2) 10 sessions of active TMS reduced SMA connectivity with the anterior cingulate, angular gyrus and the medial temporal cortex, whereas sham TMS did not reduce SMA connectivity. From a behavioral perspective, both groups showed nFOG-Q improvements (F(4, 25.7) = 3.87, p = 0.014). CONCLUSIONS: The SMA in freezers is hyper-connected to the cerebellum, a key locomotor region which may represent maladaptive compensation. In this preliminary study, 1 Hz rTMS reduced SMA connectivity however, this was not specific to the locomotor regions. Intervention outcomes may be improved with subject specific targeting of SMA.

State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users.

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users. However, it is known that there are individual differences in response to repetitive transcranial magnetic stimulation (rTMS), with some individuals being responders and others non-responders. There is some evidence that state-dependent effects influence response to rTMS, with baseline neural state predicting rTMS treatment outcomes. In this single-blind, active sham-controlled crossover study, we assess the striatum as a biomarker of treatment response by determining if baseline drug cue reactivity in the striatum influences striatal response to mPFC cTBS. The brain response to cocaine cues was measured in 19 cocaine-dependent individuals immediately before and after real and sham cTBS (110% resting motor threshold, 3600 total pulses). Group independent component analysis (ICA) revealed a prominent striatum network comprised of bilateral caudate, putamen, and nucleus accumbens, which was modulated by the cocaine cue reactivity task. Baseline drug cue reactivity in this striatal network was inversely related to change in striatum reactivity after real (vs. sham) cTBS treatment (ρ = -.79; p < .001; R 2 Adj = .58). Specifically, individuals with a high striatal response to cocaine cues at baseline had significantly attenuated striatal activity after real but not sham cTBS (t 9 = -3.76; p ≤ .005). These data demonstrate that the effects of mPFC cTBS on the neural circuitry of craving are not uniform and may depend on an individual's baseline frontal-striatal reactivity to cues. This underscores the importance of assessing individual variability as we develop brain stimulation treatments for addiction.

Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity.

BACKGROUND: Elevated frontal and striatal reactivity to drug cues is a transdiagnostic hallmark of substance use disorders. The goal of these experiments was to determine if it is possible to decrease frontal and striatal reactivity to drug cues in both cocaine users and heavy alcohol users through continuous theta burst stimulation (cTBS) to the left ventromedial prefrontal cortex (VMPFC). METHODS: Two single-blinded, within-subject, active sham-controlled experiments were performed wherein neural reactivity to drug/alcohol cues versus neutral cues was evaluated immediately before and after receiving real or sham cTBS (110% resting motor threshold, 3600 pulses, Fp1 location; N = 49: 25 cocaine users [experiment 1], 24 alcohol users [experiment 2]; 196 total functional magnetic resonance imaging scans). Generalized psychophysiological interaction and three-way repeated-measures analysis of variance were used to evaluate cTBS-induced changes in drug cue-associated functional connectivity between the left VMPFC and eight regions of interest: ventral striatum, left and right caudate, left and right putamen, left and right insula, and anterior cingulate cortex. RESULTS: In both experiments, there was a significant interaction between treatment (real/sham) and time (pre/post). In both experiments, cue-related functional connectivity was significantly attenuated following real cTBS versus sham cTBS. There was no significant interaction with region of interest for either experiment. CONCLUSIONS: This is the first sham-controlled investigation to demonstrate, in two populations, that VMPFC cTBS can attenuate neural reactivity to drug and alcohol cues in frontostriatal circuits. These results provide an empirical foundation for future clinical trials that may evaluate the efficacy, durability, and clinical implications of VMPFC cTBS to treat addictions.

Author Correction: Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals.

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Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals.

Transcranial magnetic stimulation (TMS) can stimulate cortical and subcortical brain regions. However, in order to reach subcortical targets, intact monosynaptic connections are required. The goal of this investigation was to evaluate the contribution of white matter integrity and gray matter volume to frontal pole TMS-evoked striatal activity in a large cohort of chronic cocaine users. 49 cocaine users received single pulses of TMS to the frontal pole while BOLD data were acquired - a technique known as interleaved TMS/fMRI. Diffusion tensor imaging and voxel-based morphometry were used to quantify white matter integrity and gray matter volume (GMV), respectively. Stepwise regression was used to evaluate the contribution of clinical and demographic variables to TMS-evoked BOLD. Consistent with previous studies, frontal pole TMS evoked activity in striatum and salience circuitry. The size of the TMS-evoked response was related to fractional anisotropy between the frontal pole and putamen and GMV in the left frontal pole and left ACC. This is the first study to demonstrate that the effect of TMS on subcortical activity is dependent upon the structural integrity of the brain. These data suggest that these structural neuroimaging data types are biomarkers for TMS-induced mobilization of the striatum.

Functional independence in resting-state connectivity facilitates higher-order cognition.

Growing evidence suggests that intrinsic functional connectivity (i.e. highly structured patterns of communication between brain regions during wakeful rest) may encode cognitive ability. However, the generalizability of these findings is limited by between-study differences in statistical methodology and cognitive domains evaluated. To address this barrier, we evaluated resting-state neural representations of multiple cognitive domains within a relatively large normative adult sample. Forty-four participants (mean(sd) age=31(10) years; 18 male and 26 female) completed a resting-state functional MRI scan and neuropsychological assessments spanning motor, visuospatial, language, learning, memory, attention, working memory, and executive function performance. Robust linear regression related cognitive performance to resting-state connectivity among 200 a priori determined functional regions of interest (ROIs). Only higher-order cognitions (such as learning and executive function) demonstrated significant relationships between brain function and behavior. Additionally, all significant relationships were negative - characterized by moderately positive correlations among low performers and weak to moderately negative correlations among high performers. These findings suggest that functional independence among brain regions at rest facilitates cognitive performance. Our interpretation is consistent with graph theoretic analyses which represent the brain as independent functional nodes that undergo dynamic reorganization with task demand. Future work will build upon these findings by evaluating domain-specific variance in resting-state neural representations of cognitive impairment among patient populations.

Task-dependent recruitment of intrinsic brain networks reflects normative variance in cognition.

BACKGROUND: Functional neuroimaging has great potential to inform clinical decisions, whether by identifying neural biomarkers of illness progression and severity, predicting therapeutic response, or selecting suitable patients for surgical interventions. Yet a persisting barrier to functional neuroimaging's clinical translation is our incomplete understanding of how normative variance in cognition, personality, and behavior shape the brain's structural and functional organization. We propose that modeling individual differences in these brain-behavior relationships is crucial for improving the accuracy of neuroimaging biomarkers for neurologic and psychiatric disorders. METHODS: We addressed this goal by initiating the Cognitive Connectome Project, which bridges neuropsychology and neuroimaging by pairing nine cognitive domains typically assessed by clinically validated neuropsychological measures with those tapped by canonical neuroimaging tasks (motor, visuospatial perception, attention, language, memory, affective processing, decision making, working memory, and executive function). To date, we have recruited a diverse sample of 53 participants (mean [SD], age = 32 [9.7] years, 31 females). RESULTS: As a proof of concept, we first demonstrate that our neuroimaging task battery can replicate previous findings that task performance recruits intrinsic brain networks identified during wakeful rest. We then expand upon these previous findings by showing that the extent to which these networks are recruited by task reflects individual differences in cognitive ability. Specifically, performance on the Judgment of Line Orientation task (a clinically validated measure of visuospatial perception) administered outside of the MRI scanner predicts the magnitude of task-induced activity of the dorsal visual network when performing a direct replication of this task within the MRI scanner. Other networks (such as default mode and right frontoparietal) showed task-induced changes in activity that were unrelated to task performance, suggesting these networks to not be involved in visuospatial perception. CONCLUSION: These findings establish a methodological framework by which clinical neuropsychology and functional neuroimaging may mutually inform one another, thus enhancing the translation of functional neuroimaging into clinical decision making.

Merging clinical neuropsychology and functional neuroimaging to evaluate the construct validity and neural network engagement of the n-back task.

The n-back task is a widely used neuroimaging paradigm for studying the neural basis of working memory (WM); however, its neuropsychometric properties have received little empirical investigation. The present study merged clinical neuropsychology and functional magnetic resonance imaging (fMRI) to explore the construct validity of the letter variant of the n-back task (LNB) and to further identify the task-evoked networks involved in WM. Construct validity of the LNB task was investigated using a bootstrapping approach to correlate LNB task performance across clinically validated neuropsychological measures of WM to establish convergent validity, as well as measures of related but distinct cognitive constructs (i.e., attention and short-term memory) to establish discriminant validity. Independent component analysis (ICA) identified brain networks active during the LNB task in 34 healthy control participants, and general linear modeling determined task-relatedness of these networks. Bootstrap correlation analyses revealed moderate to high correlations among measures expected to converge with LNB (|ρ|≥ 0.37) and weak correlations among measures expected to discriminate (|ρ|≤ 0.29), controlling for age and education. ICA identified 35 independent networks, 17 of which demonstrated engagement significantly related to task condition, controlling for reaction time variability. Of these, the bilateral frontoparietal networks, bilateral dorsolateral prefrontal cortices, bilateral superior parietal lobules including precuneus, and frontoinsular network were preferentially recruited by the 2-back condition compared to 0-back control condition, indicating WM involvement. These results support the use of the LNB as a measure of WM and confirm its use in probing the network-level neural correlates of WM processing.