Structural alterations of the motor cortex and higher order cortical areas suggest early neurodevelopmental origin of catatonia in schizophrenia.

The neurobiology of catatonia is still poorly understood. Particularly structural MRI studies yielded conflicting results. Heterogeneity of findings was suggested to stem from specifics of different rating scales. This study sought to test grey matter differences between patients with catatonia, patients without catatonia, and healthy controls using the two main instruments of catatonia rating. We included 98 patients with schizophrenia spectrum disorders and 42 healthy controls. Catatonia was measured using the Bush Francis Catatonia Rating Scale and the Northoff Catatonia Rating Scale. According to these scales, patients were classified into those with and those without catatonia. We tested whole brain grey matter volume, cortical thickness, and local gyrification across groups. Both catatonia rating scales correlated at tau = 0.65 but failed to classify identical subjects as catatonia patients. However, group differences in grey matter parameters were broadly similar with either rating scale to identify catatonia cases. Catatonia patients had reduced grey matter volume compared to controls in a large network including orbitofrontal cortex, cingulate, thalamus, and amygdala. While there was no group difference in cortical thickness, catatonia patients had increased local gyrification in premotor, motor, and parietal cortices compared to controls. Hypergyrification of the motor cortex and higher order cortical areas was found in catatonia patients compared to patients without catatonia. Both catatonia rating scales find similar symptom severity and group differences in grey matter indices. Catatonia is linked to reduced grey matter volume and increased local gyrification, suggesting some impact of early neurodevelopmental insults

The pathobiology of psychomotor slowing in psychosis: altered cortical excitability and connectivity.

Psychomotor slowing is a frequent symptom of schizophrenia. Short-interval intracortical inhibition assessed by transcranial magnetic stimulation demonstrated inhibitory dysfunction in schizophrenia. The inhibitory deficit results from additional noise during information processing in the motor system in psychosis. Here, we tested whether cortical inhibitory dysfunction was linked to psychomotor slowing and motor network alterations. In this cross-sectional study, we included 60 patients with schizophrenia and psychomotor slowing determined by the Salpêtrière Retardation Rating Scale, 23 patients without slowing and 40 healthy control participants. We acquired single and double-pulse transcranial magnetic stimulation effects from the left primary motor cortex, resting-state functional connectivity and diffusion imaging on the same day. Groups were compared on resting motor threshold, amplitude of the motor evoked potentials, as well as short-interval intracortical inhibition. Regression analyses calculated the association between motor evoked potential amplitudes or cortical inhibition with seed-based resting-state functional connectivity from the left primary motor cortex and fractional anisotropy at whole brain level and within major motor tracts. In patients with schizophrenia and psychomotor slowing, we observed lower amplitudes of motor evoked potentials, while the short-interval intracortical inhibition/motor evoked potentials amplitude ratio was higher than in healthy controls, suggesting lower cortical inhibition in these patients. Patients without slowing also had lower amplitudes of motor evoked potentials. Across the combined patient sample, cortical inhibition deficits were linked to more motor coordination impairments. In patients with schizophrenia and psychomotor slowing, lower amplitudes of motor evoked potentials were associated with lower fractional anisotropy in motor tracts. Moreover, resting-state functional connectivity between the primary motor cortex, the anterior cingulate cortex and the cerebellum increased with stronger cortical inhibition. In contrast, in healthy controls and patients without slowing, stronger cortical inhibition was linked to lower resting-state functional connectivity between the left primary motor cortex and premotor or parietal cortices. Psychomotor slowing in psychosis is linked to less cortical inhibition and aberrant functional connectivity of the primary motor cortex. Higher neural noise in the motor system may drive psychomotor slowing and thus may become a treatment target

Psychomotor slowing alters gait velocity, cadence, and stride length and indicates negative symptom severity in psychosis.

Schizophrenia is a severe mental disorder, in which 50% of the patients present with motor abnormalities such as psychomotor slowing. Slow spontaneous gait has been reported in schizophrenia. However, comprehensive objective instrumental assessments of multiple gait conditions are missing. Finally, the specific gait patterns of subjects with psychomotor slowing are still unknown. Therefore, this study aimed to objectively assess multiple gait parameters at different walking conditions in patients with schizophrenia with and without psychomotor slowing. Also, we hypothesised gait impairments to correlate with expert ratings of hypokinetic movement disorders and negative symptoms. We collected gait data (GAITRite®) in 70 patients with psychomotor slowing (SRRS (Salpetriere retardation rating scale) ≥15), 22 non-psychomotor slowed patients (SRRS  16.18, all p < 0.001). Secondly, slower velocity was associated with more severe hypokinetic movement disorders and negative symptoms. In conclusion, gait impairments exist in a spectrum with healthy controls on one end and patients with psychomotor slowing on the other end. Patients with psychomotor slowing are specifically impaired when an adaptation of gait patterns is required, contributing to the deleterious effects of sedentary behaviours

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Test-retest reliability of resting-state cerebral blood flow quantification using pulsed Arterial Spin Labeling (PASL) over 3 weeks vs 8 weeks in healthy controls.

Arterial Spin Labeling is a valuable functional imaging tool for both clinical and research purposes. However, little is known about the test-retest reliability of cerebral blood flow measurements over longer periods. In this study, we investigated the reliability of pulsed Arterial Spin Labeling in assessing cerebral blood flow over a 3 (n = 28) vs 8 (n = 19) weeks interscan interval in 47 healthy participants. As a measure of cerebral blood flow reliability, we calculated voxel-wise, whole-brain, and regions of interest intraclass correlation coefficients. The whole-brain mean resting-state cerebral blood flow showed good to excellent reliability over time for both periods (intraclass correlation coefficients = 0.85 for the 3-week delay, intraclass correlation coefficients = 0.53 for the 8-week delay). However, the voxel-wise and regions of interest intraclass correlation coefficients fluctuated at 8-week compared to the 3-week interval, especially within cortical areas. These results confirmed previous findings that Arterial Spin Labeling could be used as a reliable method to assess brain perfusion. However, as the reliability seemed to decrease over time, caution is warranted when performing correlations with other variables, especially in clinical populations

Psychomotor Slowing in Psychosis and Inhibitory Repetitive Transcranial Magnetic Stimulation: A Randomized Clinical Trial.

IMPORTANCE Psychomotor slowing is a frequent symptom of psychosis, impairing gross and fine motor behavior. It is associated with poor outcomes and functioning, and no treatment is available. OBJECTIVE To investigate whether 15 sessions of inhibitory repetitive transcranial magnetic stimulation (rTMS) may reduce psychomotor slowing. DESIGN, SETTING, AND PARTICIPANTS This was a 4-arm, double-blind, randomized, sham-controlled trial at a university hospital in Switzerland. Enrollment took place from March 2019 to August 2022. Adults aged 18 to 60 years with schizophrenia spectrum disorders and severe psychomotor slowing were eligible. All patients continued existing medications, including antipsychotics and benzodiazepines. Those with substance misuse (other than nicotine), conditions associated with impaired or aberrant movement, convulsions, history of hearing problems, other conditions typically excluded from magnetic resonance imaging or TMS, any TMS treatment in the past 3 months, or those who were pregnant or breastfeeding were excluded. Of 615 patients screened for eligibility, 103 were randomized and 88 received at least 1 session of rTMS: 22 were assigned to 1-Hz rTMS, 22 to iTBS, 22 to sham, and 22 to the waiting group. Follow-up was conducted at 6 weeks and 24 weeks following the week 3 assessments including clinical, functional, and motor measures. INTERVENTIONS Fifteen sessions of rTMS in 3 weeks over the supplementary motor area: 1-Hz rTMS, iTBS, sham, or no treatment (waiting). After 3 weeks, the waiting group received 15 sessions of 1-Hz rTMS over the supplementary motor area. MAIN OUTCOMES AND MEASURES The main outcome was the proportion of responders at week 3 in the Salpêtrière Retardation Rating Scale (SRRS) defined as a 30% or greater reduction from baseline (last-observation-carried-forward). The SRRS has 15 items and a maximum total score of 60. RESULTS Of the 88 participants analyzed, 45 were men and 43 were women. The mean (SD) age was 36.3 (12.4) years and the mean (SD) SRRS score was 24.0 (5.9). A total of 69 participants completed the study. At week 3, response rates differed between groups: 15 of 22 (68%) in the 1-Hz rTMS group, 8 of 22 (36%) in the iTBS group, 7 of 22 (32%) in the sham group, and 4 of 22 (18%) in the waiting group (χ23 = 12.1; P = .007). The 1-Hz rTMS group had more responders than sham (odds ratio [OR], 0.13; 95% CI, 0.02-0.65; P = .03), iTBS (OR, 0.12; 95% CI, 0.02-0.61; P = .02), and waiting (OR, 0.04; 95% CI, 0.01-0.22; P = .003). In the waiting group, 10 of 16 participants (63%) responded after receiving 15 sessions of 1-Hz rTMS. No serious adverse events occurred. CONCLUSIONS AND RELEVANCE In this study, inhibitory add-on rTMS safely alleviated psychomotor slowing in psychosis compared with iTBS, sham, and no treatment. The treatment was also effective with delayed onset. Future studies need to explore the neural changes associated with supplementary motor area rTMS in psychosis. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03921450