Lesions causing freezing of gait localize to a cerebellar functional network.

OBJECTIVE: Freezing of gait is a disabling symptom in Parkinson disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation. METHODS: Fourteen cases of lesion-induced freezing of gait were identified from the literature, and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion-induced disorders. RESULTS: Lesion location was heterogeneous, and no single region could be considered necessary for symptom generation. However, > 90% (13 of 14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis). INTERPRETATION: Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson disease patients, advancing our understanding of the brain regions involved in freezing of gait. ANN NEUROL 2017;81:129-141.

Network-targeted cerebellar transcranial magnetic stimulation improves attentional control.

Developing non-invasive brain stimulation interventions to improve attentional control is extremely relevant to a variety of neurological and psychiatric populations, yet few studies have identified reliable biomarkers that can be readily modified to improve attentional control. One potential biomarker of attention is functional connectivity in the core cortical network supporting attention - the dorsal attention network (DAN). We used a network-targeted cerebellar transcranial magnetic stimulation (TMS) procedure, intended to enhance cortical functional connectivity in the DAN. Specifically, in healthy young adults we administered intermittent theta burst TMS (iTBS) to the midline cerebellar node of the DAN and, as a control, the right cerebellar node of the default mode network (DMN). These cerebellar targets were localized using individual resting-state fMRI scans. Participants completed assessments of both sustained (gradual onset continuous performance task, gradCPT) and transient attentional control (attentional blink) immediately before and after stimulation, in two sessions (cerebellar DAN and DMN). Following cerebellar DAN stimulation, participants had significantly fewer attentional lapses (lower commission error rates) on the gradCPT. In contrast, stimulation to the cerebellar DMN did not affect gradCPT performance. Further, in the DAN condition, individuals with worse baseline gradCPT performance showed the greatest enhancement in gradCPT performance. These results suggest that temporarily increasing functional connectivity in the DAN via network-targeted cerebellar stimulation can enhance sustained attention, particularly in those with poor baseline performance. With regard to transient attention, TMS stimulation improved attentional blink performance across both stimulation sites, suggesting increasing functional connectivity in both networks can enhance this aspect of attention. These findings have important implications for intervention applications of TMS and theoretical models of functional connectivity.