Improving efficacy of repetitive transcranial magnetic stimulation for treatment of Parkinson disease gait disorders.

Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitive-motor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal ganglia-cortex-cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP.

Repeated spaced cortical paired associative stimulation promotes additive plasticity in the human parietal-motor circuit.

OBJECTIVE: Repeated spaced sessions of repetitive transcranial magnetic stimulation (TMS) to the human primary motor cortex can lead to dose-dependent increases in motor cortical excitability. However, this has yet to be demonstrated in a defined cortical circuit. We aimed to examine the effects of repeated spaced cortical paired associative stimulation (cPAS) on excitability in the motor cortex. METHODS: cPAS was delivered to the primary motor cortex (M1) and posterior parietal cortex (PPC) with two coils. In the multi-dose condition, three sessions of cPAS were delivered 50-min apart. The single-dose condition had one session of cPAS, followed by two sessions of a control cPAS protocol. Motor-evoked potentials were evaluated before and up to 40 min after each cPAS session as a measure of cortical excitability. RESULTS: Compared to a single dose of cPAS, motor cortical excitability significantly increased after multi-dose cPAS. Increasing the number of cPAS sessions resulted in a cumulative, dose-dependent effect on excitability in the motor cortex, with each successive cPAS session leading to notable increases in potentiation. CONCLUSION: Repeated spaced cPAS sessions summate to increase motor cortical excitability induced by single cPAS. SIGNIFICANCE: Repeated spaced cPAS could potentially restore abilities lost due to disorders like stroke.

Neuromodulatory transcranial magnetic stimulation (TMS) changes functional connectivity proportional to the electric-field induced by the TMS pulse.

OBJECTIVE: Transcranial magnetic stimulation (TMS) can efficiently and robustly modulate synaptic plasticity, but little is known about how TMS affects functional connectivity (rs-fMRI). Accordingly, this project characterized TMS-induced rsFC changes in depressed patients who received 3 days of left prefrontal intermittent theta burst stimulation (iTBS). METHODS: rs-fMRI was collected from 16 subjects before and after iTBS. Correlation matrices were constructed from the cleaned rs-fMRI data. Electric-field models were conducted and used to predict pre-post changes in rs-fMRI. Site by orientation heatmaps were created for vectors centered on the stimulation site and a control site (contralateral motor cortex). RESULTS: For the stimulation site, there was a clear relationship between both site and coil orientation, and connectivity changes. As distance from the stimulation site increased, prediction accuracy decreased. Similarly, as eccentricity from the optimal orientation increased, prediction accuracy decreased. The systematic effects described above were not apparent in the heatmap centered on the control site. CONCLUSIONS: These results suggest that rs-fMRI following iTBS changes systematically as a function of the distribution of electrical energy delivered from the TMS pulse, as represented by the e-field model. SIGNIFICANCE: This finding lays the groundwork for future studies to individualize TMS targeting based on how predicted rs-fMRI changes might impact psychiatric symptoms.

The behavioral and neural effects of parietal theta burst stimulation on the grasp network are stronger during a grasping task than at rest.

Repetitive transcranial magnetic stimulation (TMS) is widely used in neuroscience and clinical settings to modulate human cortical activity. The effects of TMS on neural activity depend on the excitability of specific neural populations at the time of stimulation. Accordingly, the brain state at the time of stimulation may influence the persistent effects of repetitive TMS on distal brain activity and associated behaviors. We applied intermittent theta burst stimulation (iTBS) to a region in the posterior parietal cortex (PPC) associated with grasp control to evaluate the interaction between stimulation and brain state. Across two experiments, we demonstrate the immediate responses of motor cortex activity and motor performance to state-dependent parietal stimulation. We randomly assigned 72 healthy adult participants to one of three TMS intervention groups, followed by electrophysiological measures with TMS and behavioral measures. Participants in the first group received iTBS to PPC while performing a grasping task concurrently. Participants in the second group received iTBS to PPC while in a task-free, resting state. A third group of participants received iTBS to a parietal region outside the cortical grasping network while performing a grasping task concurrently. We compared changes in motor cortical excitability and motor performance in the three stimulation groups within an hour of each intervention. We found that parietal stimulation during a behavioral manipulation that activates the cortical grasping network increased downstream motor cortical excitability and improved motor performance relative to stimulation during rest. We conclude that constraining the brain state with a behavioral task during brain stimulation has the potential to optimize plasticity induction in cortical circuit mechanisms that mediate movement processes.

Cortical-subcortical structural connections support transcranial magnetic stimulation engagement of the amygdala.

The amygdala processes valenced stimuli, influences emotion, and exhibits aberrant activity across anxiety disorders, depression, and PTSD. Interventions modulating amygdala activity hold promise as transdiagnostic psychiatric treatments. In 45 healthy participants, we investigated whether transcranial magnetic stimulation (TMS) elicits indirect changes in amygdala activity when applied to ventrolateral prefrontal cortex (vlPFC), a region important for emotion regulation. Harnessing in-scanner interleaved TMS/functional MRI (fMRI), we reveal that vlPFC neurostimulation evoked acute and focal modulations of amygdala fMRI BOLD signal. Larger TMS-evoked changes in the amygdala were associated with higher fiber density in a vlPFC-amygdala white matter pathway when stimulating vlPFC but not an anatomical control, suggesting this pathway facilitated stimulation-induced communication between cortex and subcortex. This work provides evidence of amygdala engagement by TMS, highlighting stimulation of vlPFC-amygdala circuits as a candidate treatment for transdiagnostic psychopathology. More broadly, it indicates that targeting cortical-subcortical structural connections may enhance the impact of TMS on subcortical neural activity and, by extension, subcortex-subserved behaviors.

Resting fMRI-guided TMS results in subcortical and brain network modulation indexed by interleaved TMS/fMRI.

Traditional non-invasive imaging methods describe statistical associations of functional co-activation over time. They cannot easily establish hierarchies in communication as done in non-human animals using invasive methods. Here, we interleaved functional MRI (fMRI) recordings with non-invasive transcranial magnetic stimulation (TMS) to map causal communication between the frontal cortex and subcortical target structures including the subgenual anterior cingulate cortex (sgACC) and the amygdala. Seed-based correlation maps from each participant's resting fMRI scan determined individual stimulation sites with high temporal correlation to targets for the subsequent TMS/fMRI session(s). The resulting TMS/fMRI images were transformed to quantile responses, so that regions of high-/low-quantile response corresponded to the areas of the brain with the most positive/negative evoked response relative to the global brain response. We then modeled the average quantile response for a given region (e.g., structure or network) to determine whether TMS was effective in the relative engagement of the downstream targets. Both the sgACC and amygdala were differentially influenced by TMS. Furthermore, we found that the sgACC distributed brain network was modulated in response to fMRI-guided TMS. The amygdala, but not its distributed network, also responded to TMS. Our findings suggest that individual targeting and brain response measurements reflect causal circuit mapping to the sgACC and amygdala in humans. These results set the stage to further map circuits in the brain and link circuit pathway integrity to clinical intervention outcomes, especially when the intervention targets specific pathways and networks as is possible with TMS.

Combining transcranial magnetic stimulation with functional magnetic resonance imaging for probing and modulating neural circuits relevant to affective disorders.

Combining transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging offers an unprecedented tool for studying how brain networks interact in vivo and how repetitive trains of TMS modulate those networks among patients diagnosed with affective disorders. TMS compliments neuroimaging by allowing the interrogation of causal control among brain circuits. Together with TMS, neuroimaging can provide valuable insight into the mechanisms underlying treatment effects and downstream circuit communication. Here we provide a background of the method, review relevant study designs, consider methodological and equipment options, and provide statistical recommendations. We conclude by describing emerging approaches that will extend these tools into exciting new applications. This article is categorized under: Psychology > Emotion and Motivation Psychology > Theory and Methods Neuroscience > Clinical Neuroscience.