Effect of rTMS Over the Medial Cerebellum on Negative Symptoms and Cognitive Dysmetria in Subjects With Treatment Refractory Schizophrenia

Background and Significance

There is increasing evidence from neuropsychological and imaging studies that cerebellar function is relevant not only to motor coordination, but equally to cognition and behavior (Rapoport et al., 2000). Selective modulation of cerebello-thalamocortical pathways, in turn, is believed to provide an additional means of modulating cortical function. Repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability focally in conscious subjects. Trains with slow frequency (i.e.,1 Hz) are known to suppress cortical excitability (Chen et al., 1997), whereas facilitation occurs if frequencies higher than 5 Hz are used (Berardelli et al., 1998). With respect to rTMS of the cerebellum, a major impact on cognitive function (Oliveri et al., 2007) has been described.

The cerebellum is a very good candidate to be the generator for intracortical inhibition; its stimulation can modulate the cortical inhibition. Invasive studies by Robert Heath at Tulane University revealed that the cerebellum is strongly connected to 2 structures at the core of the proposed abnormal circuitry in schizophrenia, the septal nuclei and the hippocampus (HC). According to his theory and findings, the septal nuclei are involved in positive mood regulation, pleasure. The firing of the HC was correlated with negative affect and sadness (Heath et al, 1980). By stimulating the fastigial nucleus and vermis of the cerebellum, the septal nuclei were facilitated to fire and the HC was inhibited. The other component of what Heath referred to as the "aversive system", the amygdala was also inhibited. This central role of the cerebellum in this circuit is analogous to its role in "smoothing" the flow of movements. When considering emotion and cognition, the cerebellum has a smoothing function. Aside from direct monosynaptic connections between these sites, there is evidence that the deep cerebellar nuclei are connected to the parietal cortex, temporal cortex, as well as the cingulate gyrus. These are all areas that have limbic function. The cerebellum is also directly connected to the midbrain reticular activating system (RAS). This region is responsible for levels of consciousness and arousal. By potentiating the activation of the RAS, wthe investigators e can increase the decreased level of arousal, which in many schizophrenia patients is akin to psychomotor retardation and mutism (catatonic). Midline deep cerebellar nuclei efferents have been traced to the hypothalamus, central nuclei of the thalamus, which are also associative (cognitive) and limbic in function. The Locus Ceruleus and the substantia nigra, in the brain stem are also monosynaptically connected to the cerebellum.

The cerebellum is connected to thalamus and motor cortex (frontal cortex) through cerebello-thalamo-cortical pathway. And as stated above it is also connected to a vast array of limbic structures, making it a good choice to use to modulate abnormal activity in these structures.

Purkinje cells, the output neurons of cerebellar cortex reduce the excitatory drive from the deep cerebellar nuclei via the ventrolateral thalamus to inhibitory neurons in the motor cortex. Activation of Purkinje cells will inhibit the thalamic drive to intracortical inhibitory neurons, therefore, decrease the intracortical inhibitory interneuron activity and decrease in SICI and CSP. On the other hand, inhibition of Purkinje cerebellar cells is expected to have opposite effect and release the thalamus from inhibitory control, increase the thalamic drive to stimulate the inhibitory interneurons which can be demonstrated by increase in SICI and CSP Indeed, applying inhibitory rTMS at frequency of 1 Hz resulted in increase in SICI (Langguth et al., 2008).