Stimulation for the compact parts of pedunculopontine nucleus: An available therapeutic approach in intractable epilepsy

Many studies have shown that susceptibility to epilepsy is increased during nonrapid eye movement (NREM, slow-wave) sleep whereas rapid eyemovement (REM) sleep suppresses seizure occurrence. Therefore, it is postulated that rapid eye movement sleep is a natural antiepileptogenic system in the body during the human wake–sleep cycle [1–3]. Because it is demonstrated that stimulation of the pedunculopontine tegmental nucleus (PPTg) can enhance REM sleep successfully [4], PPTg has been highlighted as a target for deep brain stimulation for seizure treatment of intractable epilepsy [2,5,6]; however, the exact location of the optimal brain site for stimulation is not fully understood [7,8]. Recently, some studies have suggested that the neurons innervating motor structures are predominantly situated in the caudal parts of the PPTg, which divide into the dissipated part (dp) and compact part (cp) of the PPTg [9–11]. Nevertheless, it is still unclear whether cpPPTg or dpPPTg is tightly linked to motor projections. There is unequivocal agreement on the high and specific value of neurotropic pseudorabies virus (PRV) tracing for synaptic connectivity and neuroanatomical pathways in CNS by propagating retrogradely through chains of functionally connected neurons [11–16]. It is well known that PRV can provide a highly specific method of mapping the motor and sympathetic pathways innervating a variety of targets [12,17–19]. We explore the hypothesis that the functional integrity of synapses in the cpPPTg is essential tomotor projections andnot sympathetic projections. We had characterized projections from the left gastrocnemius muscle to the PPTg of the midbrain tegmentum in surgically sympathectomized [20,21]mice by using retrograde tracing techniques of PRV-614, expressing a novelmonomeric red fluorescent protein (mRFP1) under control of the cytomegalovirus immediate early promoter for direct visualization with the fluorescence microscope [22–24]. We found that injections of PRV-614 into the left gastrocnemius muscle labeled neurons in the cpPPTg and dpPPTg (Fig. 1), which was in line with a previous report showing that the PPTg control of the lumbar epaxial muscle produced a special posture by transneuronal tracer PRV-Bartha [25], suggesting that a direct neuronal circuit from the cpPPTg and dpPPTg to gastrocnemius muscle exists via the motor pathway. Otherwise, PRV-614/tyrosine hydroxylase (TH) and PRV614/tryptophan hydroxylase (TPH) double-labeled neurons were detected in the dpPPTg and not in the cpPPTg (Fig. 1), which was in agreement with our previous immunohistochemical study in investigating that PRV-614/tryptophan hydroxylase and PRV-614/tyrosine hydroxylase double-labeled neurons in the cpPPTg were not detected