Central serotonergic function in patients with predominantly negative symptoms of schizophrenia

The serotonergic system plays a crucial role in the pathophysiology of various psychiatric disorders, including major depression, obsessive-compulsive disorder, anxiety disorders, and schizophrenia (Lucki, 1998). Therefore, reliable indicators of central serotonergic neurotransmission, particularly of synaptically released serotonin, are of high clinical relevance for diagnostic and therapeutic purposes (Hegerl, Gallinat, & Juckel, 2001). Such an indicator could help to identify individual patients with a serotonergic dysfunction and to select more specific pharmacological interventions that are associated with better treatment outcome. Peripheral functional measures such as monoamine or monoamine metabolite levels in serum and cerebrospinal fluid have been shown to be nonspecific as they only partially reflect central serotonergic activity (Murphy, 1990; Potter & Manji, 1993). In the following years, research efforts focused on neurophysiological measures to assess central serotonergic function. In particular, preclinical and clinical studies in animals and humans indicated that the loudness dependence of auditory evoked potentials is related to the serotonergic neurotransmission in the primary auditory cortex and might therefore be a promising in vivo biomarker of central serotonergic activity.

Neural information processing is subject to noise and this leads to variability in neural firing and behavior. Schizophrenia has been associated with both more variable motor control and impaired cortical inhibition, which is crucial for excitatory/inhibitory balance in neural commands.

In this study, we hypothesized that impaired intracortical inhibition in motor cortex would contribute to task-related motor noise in schizophrenia.

We measured variability of force and of electromyographic (EMG) activity in upper limb and hand muscles during a visuomotor grip force-tracking paradigm in patients with schizophrenia (N = 25), in unaffected siblings (N = 17) and in healthy control participants (N = 25). Task-dependent primary motor cortex (M1) excitability and inhibition were assessed using transcranial magnetic stimulation (TMS).

During force maintenance patients with schizophrenia showed increased variability in force and EMG, despite similar mean force and EMG magnitudes. Compared to healthy controls, patients with schizophrenia also showed increased M1 excitability and reduced cortical inhibition during grip-force tracking. EMG variability and force variability correlated negatively to cortical inhibition in patients with schizophrenia. EMG variability also correlated positively to negative symptoms. Siblings had similar variability and cortical inhibition compared to controls. Increased EMG and force variability indicate enhanced motor noise in schizophrenia, which relates to reduced motor cortex inhibition.

The findings suggest that excessive motor noise in schizophrenia may arise from an imbalance of M1 excitation/inhibition of GABAergic origin. Thus, higher motor noise may provide a useful marker of impaired cortical inhibition in schizophrenia.