Objective: The dopamine hypothesis is one of the most influential theories of the neurobiological background of schizophrenia (SCZ). However, direct evidence for abnormal dopamine-related subcortical-cortical circuitry disconnectivity is still lacking. The aim of this study was therefore to test dopamine-related substantia nigra (SN)-based striato-thalamo-cortical resting-state functional connectivity (FC) in SCZ. Method: Based on our a priori hypothesis, we analyzed a large sample resting-state functional magnetic resonance imaging (fMRI) dataset from first-episode drug-naïve SCZ patients (n = 112) and healthy controls (n (...) = 82) using the SN as the seed region for an investigation of striato-thalamo-cortical FC. This was done in the standard band of slow frequency oscillations and then in its subfrequency bands (Slow4 and Slow5). Results: The analysis showed in SCZ: (1) reciprocal functional hypo-connectivity between SN and striatum, with differential patterns for Slow5 and Slow4; (2) functional hypo-connectivity between striatum and thalamus, as well as functional hyper-connectivity between thalamus and sensorimotor cortical areas, specifically in Slow4; (3) correlation of thalamo-sensorimotor functional hyper-connectivity with psychopathological symptoms. Conclusions: We demonstrate abnormal dopamine-related SN-based striato-thalamo-cortical FC in slow frequency oscillations in first-episode drug-naive SCZ. This suggests that altered dopaminergic function in the SN leads to abnormal neuronal synchronization (as indexed by FC) within subcortical-cortical circuitry, complementing the dopamine hypothesis in SCZ on the regional level of resting-state activity. (shrink)

Aspects of Northoff's argument lend themselves to the ongoing investigation of localizing the self in the brain. Recent data from the fields of neuropsychology and cognitive neuroscience provide evidence that the right hemisphere is a candidate for localization of self. The data on catatonia further that proposition and add insight into the continuing investigation of self in the brain across sensory and motor domains.

We argue that the pivotal role assigned by Northoff to the principle of top-down modulation in catatonia might successfully be applied to other symptoms of schizophrenia, for example, hallucinations. Second, we propose that Northoff's account would benefit from a more comprehensive analysis of the cognitive level of explanation. Finally, contrary to Northoff, we hypothesize that “top-down modulation” might play as important a role as “horizontal modulation” in affective-behavioral alterations.

Differential diagnosis of motor symptoms, for example, akinesia, may be difficult in clinical neuropsychiatry. Symptoms may be either of neurologic origin, for example, Parkinson's disease, or of psychiatric origin, for example, catatonia, leading to a so-called “conflict of paradigms.” Despite their different origins, symptoms may appear more or less clinically similar. Possibility of dissociation between origin and clinical appearance may reflect functional brain organisation in general, and cortical-cortical/subcortical relations in particular. It is therefore hypothesized that similarities and differences between Parkinson's (...) disease and catatonia may be accounted for by distinct kinds of modulation between cortico-cortical and cortico-subcortical relations. Catatonia can be characterized by concurrent motor, emotional, and behavioural symptoms. The different symptoms may be accounted for by dysfunction in orbitofrontal-prefrontal/parietal cortical connectivity reflecting “horizontal modulation” of cortico-cortical relation. Furthermore, alteration in “top-down modulation” reflecting “vertical modulation” of caudate and other basal ganglia by GABA-ergic mediated orbitofrontal cortical deficits may account for motor symptoms in catatonia. Parkinson's disease, in contrast, can be characterized by predominant motor symptoms. Motor symptoms may be accounted for by altered “bottom-up modulation” between dopaminergic mediated deficits in striatum and premotor/motor cortex. Clinical similarities between Parkinson's disease and catatonia with respect to akinesia may be related with involvement of the basal ganglia in both disorders. Clinical differences with respect to emotional and behavioural symptoms may be related with involvement of different cortical areas, that is, orbitofrontal/parietal and premotor/motor cortex implying distinct kinds of modulation – “vertical” and “horizontal” modulation, respectively. Key Words: Bottom-up modulation; catatonia; horizontal modulation; Parkinson's disease; top-down modulation; vertical modulation. (shrink)

The intrinsic merit of Northoff's model lies primarily in the fact that it integrates data concerned with different levels of organization of the brain. This approach implicitly argues against reductionism, although, apparently, its rather simplistic assumption gives too many degrees of freedom. In considering that a symptom from two different syndromes indicates a common neural alteration, we grossly disregard neural plasticity.

Georg Northoff encounters a problem regarding the logical status of “catatonia.” Whereas Parkinson's disease (PD) is a disease on the basis of Virchowian criteria, catatonia is not. PD is associated with pathognomonic neurological lesions. Catatonia does not require any such association. The diagnosis is rendered using social criteria rather than neuropathological ones. Therefore, Northoff is not comparing two disease states at all.