Speculation on the responsible sites and pathophysiology of freezing of gait

Abstract Freezing of gait (FOG) is a symptom characterized by difficulty in taking the first step when a patient begins to walk; it is experienced most frequently in Parkinson's disease, and is also one of the major symptoms of gait apraxia. The brain sites responsible for FOG have not yet been determined. FOG is believed to derive from dysfunction of higher centers for human bipedal locomotion. Recent brain activation studies have suggested that the medial frontoparietal cortex, including the supplementary motor area (SMA), is a central higher center for bipedal locomotion in humans. FOG is most frequently observed in patients with Parkinson's disease, whose pathophysiology is a functional change in the motor circuit induced by dopaminergic denervation. Overactivity or altered firing patterns of the internal segment of the globus pallidus (GPi) may excessively inhibit or disorganize the thalamocortical projection, of which a major cortical target is the SMA. It has been recognized that gait apraxia is associated with mesial or medial frontal cortical lesions. Considering that the brain activation sites in human locomotion and the brain lesion sites manifesting freezing gait share common areas, the brain sites responsible for FOG are presumably located in the medial frontoparietal area. The SMA may be a major structure in the center; however, the neural network related to FOG may extend to its adjacent areas. FOG can be classified into two types, in terms of responsiveness to treatment: (1) FOG responsive to levodopa and neurosurgery targeting the subthalamic nucleus (STN) or GPi; and (2) FOG unresponsive to either levodopa or neurosurgery. The responsive type is observed in cases with less advanced Parkinson's disease, in which dysfunction of the SMA and adjacent areas can be reversed by normalization of the motor circuit function by levodopa treatment or neurosurgery. The unresponsive type is observed in advanced Parkinson's disease, primary progressive freezing gait, or frontal lobe lesions, and the underlying pathology may consist of irreversible changes of the SMA and adjacent areas, or of the structures of the motor circuit. The involvement of transmitters other than dopamine, including norepinephrine, in the pathophysiology of FOG remains undetermined.