Glutamate-Weighted Magnetic Resonance Imaging (GluCEST) Detects Effects of Transcranial Magnetic Stimulation to the Motor Cortex.

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta-burst stimulation (cTBS) is a form of TMS observed to reduce motor evoked potentials (MEPs) for 60 min or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that the gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral region of interest (ROI) or in subjects receiving sham stimulation.

Language Tasks and the Network Control Role of the Left Inferior Frontal Gyrus.

Recent work has combined cognitive neuroscience and control theory to make predictions about cognitive control functions. Here, we test a link between whole-brain theories of semantics and the role of the left inferior frontal gyrus (LIFG) in controlled language performance using network control theory (NCT), a branch of systems engineering. Specifically, we examined whether two properties of node controllability, boundary and modal controllability, were linked to semantic selection and retrieval on sentence completion and verb generation tasks. We tested whether the controllability of the left IFG moderated language selection and retrieval costs and the effects of continuous θ burst stimulation (cTBS), an inhibitory form of transcranial magnetic stimulation (TMS) on behavior in 41 human subjects (25 active, 16 sham). We predicted that boundary controllability, a measure of the theoretical ability of a node to integrate and segregate brain networks, would be linked to word selection in the contextually-rich sentence completion task. In contrast, we expected that modal controllability, a measure of the theoretical ability of a node to drive the brain into specifically hard-to-reach states, would be linked to retrieval on the low-context verb generation task. Boundary controllability was linked to selection and to the ability of TMS to reduce response latencies on the sentence completion task. In contrast, modal controllability was not linked to performance on the tasks or TMS effects. Overall, our results suggest a link between the network integrating role of the LIFG and selection and the overall semantic demands of sentence completion.

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.

Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects.

BACKGROUND: Patients with bipolar depression are characterized by dysregulation across the full spectrum of mood, differentiating them from patients with unipolar depression. The ability to switch neural resources among the default mode network, salience network, and executive control network (ECN) has been proposed as a key mechanism for adaptive mood regulation. The anterior insula is implicated in the modulation of functional network switching. Differential connectivity between anterior insula and functional networks may provide insights into pathophysiological differences between bipolar and unipolar mood disorders, with implications for diagnosis and treatment. METHODS: Resting-state functional magnetic resonance imaging data were collected from 98 subjects (35 unipolar, 24 bipolar, and 39 healthy control subjects). Pearson correlations were computed between bilateral insula seed regions and a priori defined target regions from the default mode network, salience network, and ECN. After r-to-z transformation, a one-way multivariate analysis of covariance was conducted to identify significant differences in connectivity between groups. Post hoc pairwise comparisons were conducted and Bonferroni corrections were applied. Receiver-operating characteristics were computed to assess diagnostic sensitivity. RESULTS: Patients with bipolar depression evidenced significantly altered right anterior insula functional connectivity with the inferior parietal lobule of the ECN relative to patients with unipolar depression and control subjects. Right anterior insula-inferior parietal lobule connectivity significantly discriminated patients with bipolar depression. CONCLUSIONS: Impaired functional connectivity between the anterior insula and the inferior parietal lobule of the ECN distinguishes patients with bipolar depression from those with unipolar depression and healthy control subjects. This finding highlights a pathophysiological mechanism with potential as a therapeutic target and a clinical biomarker for bipolar disorder, exhibiting reasonable sensitivity and specificity.

Resting state functional connectivity in primary insomnia, generalized anxiety disorder and controls.

Sleep abnormalities are extremely common in anxiety disorders and may contribute to their development and persistence. Their shared pathophysiological mechanisms could thus serve as biomarkers or targets for novel therapeutics. Individuals with Primary Insomnia were age- and sex-matched to controls and to persons with Generalized Anxiety Disorder. All underwent fMRI resting-state scans at 3-T. In Primary Insomnia and controls, sleep was recorded for 2 weeks using diaries and actigraphy. All participants completed state-anxiety and neuroticism inventories. Whole-brain connectivity of 6 fear- and extinction-related seeds were compared between the 3 groups using ANOVA. The only significant between-group main effect was seen for connectivity between the left amygdala seed and a bilateral cluster in the rostral anterior cingulate cortex. The latter is believed to exert top-down control over amygdala activity and their interaction may thus constitute an emotion regulatory circuit. This connectivity was significantly greatest in controls while Primary Insomnia was intermediate between that of controls and Generalized Anxiety Disorder. Across Primary Insomnia and control subjects, mean connectivity decreased with poorer sleep. Across all 3 groups, connectivity decreased with greater neuroticism and pre-scan anxiety. Decreased top-down control of the amygdala may increase risk of developing an anxiety disorder with preexisting Primary Insomnia.