Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia
Introduction
Motor symptoms are frequent features of schizophrenia. They may include parkinsonian symptoms (tremor, bradykinesia, and rigidity), catatonic symptoms of inhibition or excitation, reduced motor drive as a consequence of negative symptoms, neurological soft signs (mainly referring to impaired motor coordination), and various dyskinesias (Chatterjee et al., 1995, Wolff and O'Driscoll, 1999, Peralta and Cuesta, 2001, Tandon et al., 2009). Cerebral circuits involved in motor control have been frequently shown to be altered in schizophrenia. Evidence stems from longitudinal infant development studies (Ridler et al., 2006, Schiffman et al., 2009), studies on connectivity (Koch et al., 2008), motor sequencing (Delevoye-Turrell et al., 2003, Putzhammer et al., 2005, Exner et al., 2006) and gait analysis (Putzhammer et al., 2004). Even though motor symptoms may also result from antipsychotic treatment or disease progression, they have been repeatedly reported in never-treated, first-episode patients with schizophrenia or in persons at risk (Caligiuri et al., 1993, Chatterjee et al., 1995, Wolff and O'Driscoll, 1999, McCreadie et al., 2002, Mittal and Walker, 2007, Pappa and Dazzan, 2009, Peralta et al., 2010). Particularly, the magnitude of behavioral motor activity widely varies in schizophrenia; excessive motor agitation or reduced motor activity, even akinetic episodes, are observed (Tandon et al., 2009). In contrast to healthy controls, schizophrenia patients are less active during self-reported exercise (Brown et al., 1999, McLeod et al., 2009). Despite the impact of motor symptoms, little is known about their neurobiology. Even rarer is the literature on the neurobiology of reduced motor activity in schizophrenia.
Wrist actigraphy is an efficient tool to measure quantitative gross motor activity without distressing the patient. It is not bound to artificial laboratory settings. Activity levels in schizophrenia were shown to correlate poorly with expert ratings of psychopathology, even though negative correlations occurred between activity level and the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) negative subscore (Walther et al., 2009c). However, actigraphic parameters discriminated DSM-IV schizophrenia subtypes (Walther et al., 2009b) as well as schizophrenia from cycloid psychoses (Walther et al., 2009a).
In chronic schizophrenia, grey matter volume of the left anterior cingulate cortex correlated with the cumulative activity counts as measured by actigraphy (Farrow et al., 2005), and activity was also negatively correlated with avolition scores. Furthermore, the complexity of activity in chronic patients was positively correlated with volume of the bilateral rostro-ventral putamen (Farrow et al., 2009). In healthy subjects, motor activity as measured with actigraphy correlated with white matter integrity in motor tracts (Walther et al., 2010a).
An interesting approach to investigate functional correlates of behavior is to measure brain metabolism. Two decades ago, schizophrenia subsyndromes were related to specific perfusion patterns; for example, psychomotor poverty was negatively correlated with regional cerebral blood flow (CBF) in bilateral lateral and medial prefrontal as well as in the left parietal association cortex (Liddle et al., 1992). In addition, the authors reported positive correlations with CBF in bilateral caudate nuclei. Schizophrenia patients with the deficit syndrome were shown to have reduced perfusion in the bilateral dorsolateral prefrontal cortex (DLPFC) (Vaiva et al., 2002). Later, research focused on specific symptoms rather than syndromes (Goghari et al., 2010). In this approach, formal thought disorder in schizophrenia was shown to correlate with regional cerebral blood flow (rCBF) in language-related brain areas (Horn et al., 2009), namely the Broca and Wernicke areas. Accordingly, we wanted to identify metabolic changes associated exclusively with motor activity in schizophrenia. In particular, we suspected that neural activity of specific movement-related brain areas would be altered in schizophrenia and that these changes would be related to motor activity. Because studies on the function of the supplementary motor area (SMA) and primary motor cortex in schizophrenia yielded conflicting results (Braus et al., 1999, Braus et al., 2000, Scheuerecker et al., 2009), we expected that regions involved in voluntary action and motor control such as the striato-thalamic circuit, DLPFC and anterior cingulate cortex would be more relevant to movement generation in schizophrenia than the primary motor cortex itself. In these cortices, resting state rCBF as a measure of neuronal function should be altered in schizophrenia patients. Therefore, we used actigraphy as an objective behavioral marker of motor activity and arterial spin labeling (ASL) to measure rCBF in schizophrenia and healthy controls. We hypothesized that quantitative motor activity levels would positively correlate with resting state rCBF in the DLPFC, cingulate cortex, and basal ganglia. Because basal ganglia function is thought to be altered in schizophrenia (Graybiel, 1997), the association of the basal ganglia and motor cortices may also be modified. Therefore, we suspected the pattern of correlation to be different between patients and controls. To clarify whether rCBF alterations were located in cortical areas with altered grey matter volume, we additionally analyzed the structural magnetic resonance imaging scans for group differences and correlation with motor activity.
Section snippets
Subjects
Schizophrenia patients (8 men and 3 women) were inpatients of the University Hospital of Psychiatry. All patients were of the paranoid subtype and were taking second generation antipsychotics (risperidone, n = 5; clozapine, n = 3; olanzapine, n = 2; and quetiapine, n = 1). Inclusion criteria were diagnosis of schizophrenia according to DSM-IV, 18–65 years of age, right-handedness, inpatient treatment at the time of study and magnetic resonance imaging (MRI) compatibility. Exclusion criteria were history
Activity level
The groups differed in the magnitude of volitional motor activity during wake hours, with controls displaying higher AL over 1 day (controls: mean = 18,729, S.D. = 5224; patients: mean = 13,613, S.D.= 4840; t = 2.509, d.f. = 23, P = 0.020). AL was neither correlated with age in both groups (rS = − 0.158, P = 0.452), nor did it correlate in the schizophrenia group with chlorpromazine equivalents (rS = − 0.468, P = 0.172), duration of illness (rS = − 0.005, P = 0.989), SAS score (rS = − 0.210, P = 0.535), NCS score (rS = − 0.179, P =
Main findings
This is the first study to show an association of resting state brain perfusion and quantitative measures of volitional motor behavior of the same day. Patients displayed lower activity levels than controls during the recording day. Motor activity was not associated with age, gender, medication effects or negative syndrome scores in schizophrenia. Resting state perfusion was lower in patients in five clusters including the rostral prefrontal cortex, left temporal lobe, posterior cingulate and
Conclusions
In summary, we found the magnitude of volitional motor behavior in real life to be linked to the resting perfusion of the VA of the thalamus in controls. In schizophrenia patients, by contrast, motor activity was associated with CBF in motor relevant cortical areas including the DLPFC and rCMA. This cortical association was not present in controls, who had higher overall motor activity. The finding suggests that motor retardation in schizophrenia may be a result of a basal ganglia dysfunction,
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