The Functional Anatomy of Psychomotor Disturbances in Major Depressive Disorder

Psychomotor disturbances (PMD) are a classic feature of depressive disorder that provides rich clinical information. The aim our narrative review was to characterize the functional anatomy of PMD by summarizing findings from neuroimaging studies. We found evidence across several neuroimaging modalities that suggest involvement of fronto-striatal neurocircuitry, and monoaminergic pathways and metabolism. We suggest that PMD in major depressive disorder emerge from an alteration of limbic signals, which influence emotion, volition, higher-order cognitive functions, and movement.


Introduction
Psychomotor signs are a classic feature of major depressive disorder that already attracted attention over a century ago (1). Emil Kraepelin gave a vivid and still valid description of psychomotor disturbances (PMD) in his chapter on general symptomatology in Lehrbuch des Psychiatrie, 1907: "The psychomotor retardation, which is the most important disturbance in the depressed states of manic-depressive insanity, is probably due to a [. . .] increase in resistance [. . .] In spite of every apparent exertion, the patients cannot utter a word or at best answer only in monosyllables, and are unable to eat, stand up, or dress. As a rule they clearly recognize the enormous pressure lying upon them, which they are unable to overcome" (2).
Psychomotor disturbances in depressive disorder can be broadly classified in to four subgroups of symptoms and signs based on three available clinical rating scales designed to characterize them [CORE, motor agitation and retardation scale (MARS), Widlöcher scale] (3)(4)(5): retardation, agitation, non-interactiveness, and mental slowing ( Table 1). The symptoms and signs of PMD therefore entail a wide range of brain functions including motor performance, executive function, volition, and drive. These provide rich clinical information (i.e., diagnostic subgroup, prognosis, treatment) (6,7).
No previous review has focused specifically on neuroimaging findings related to PMD in major depressive disorder. The aim of this narrative review is to characterize the functional anatomy of PMD in major depressive disorder by summarizing findings from human neuroimaging studies that probe structure, function, neurochemistry, and connectivity. White-matter alterations (hyperintensities, WHI; and whitematter fiber integrity), are one of the most reproduced findings in mood disorders. White-matter hyperintensities (WHIs) are radiological hyperintense regions of white matter with elusive etiology in MRI images. They are primarily associated with late-life depression, but are also more common in major depressive disorder in younger age groups. The extent of WHIs correlates with illness severity, poor treatment response, and decreased psychomotor speed on several neuropsychological tests (8). White-matter tissue broadly comprises glial cells with myelin surrounding axons. Currently, the general understanding is that the WHIs alterations observed in depression arise from small vessel disease that lead to disruption of white-matter pathways (9). However, other disease mechanisms involving white-matter tissue may also lead to disruptions of specific neurocircuits and lead to psychiatric symptoms such as PMD (10).
White-matter fiber integrity can be assessed with diffusionweighted imaging. One study by Walther et al. (11) who specifically addressed psychomotor functioning in depressive disorder used diffusion-weighted magnetic resonance imaging and actigraphy -an objective measure of the general activity level in an individual. It showed that lower activity levels correlate with measures of differential myelinization in the frontal lobe and posterior cingulate region, and that there is a negative correlation between the same measures in the white matter beneath the primary motor cortex and in the parahippocampal region. The authors conclude that changes in psychomotor function in depressive disorder may be linked to changes in white matter in motor regions. Bracht et al. used diffusion-weighted imaging to investigate white-matter microstructure in relation to PMD. They found a positive association between decreased physical motor activity and alterations in paralimbic and motor midline regions not only involved in volitional movement but also involvement of ascending mesocortical dopamine pathways in clinical states with prominent PMD (12,13).
To this date, few studies have investigated the relation between gray matter volume and PMD in major depressive disorder. Current findings involve volume reductions in several pre-executive parts of the motor system. One volumetric study showed that thinning of the right presupplementary motor cortex (pre-SMA) is associated with impaired performance on a motor learning test (14). The pre-SMA is a part of the mesial premotor cortex that advances signals from the prefrontal regions, engaged in higher-order cognitive functions. In studies measuring subcortical volumes and regional shape alterations, no significant associations could be found between performance on a psychomotor task (trail making test variations) and the volumes of striatum, pallidum, and thalamus in depressed subjects (15,16). Another study found that reduced caudate nucleus volumes predicts decreased psychomotor speed in depressed subjects >50 years old (17).
Only one study, using CT, has assessed cerebrospinal fluid space size. This study found that the size of the third ventricle was associated with clinical ratings of psychomotor retardation (18).

Functional Neuroimaging
Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is currently the most prevalent method for studying neural activation patterns during experimental tasks in patients with depressive disorder. A few research teams have specifically addressed PMD using fMRI and experimental motor tasks, clinical ratings of psychomotor disturbance, or motor physiology metrics (i.e., actigraphy, reaction time). Two types of studies have been employed -task and non-task based studies. Naismith et al. (19) used a motor sequence task (button press response) to study motor learning, and found increased activation of lateral prefrontal cortex, superior temporal regions, and the cerebellum. Caligiuri et al. (20,21) studied motor execution using a manual reaction time task, and found increased activation during movement in the primary motor cortex, alongside motor asymmetry. Five other studies investigated motor speed using different finger-tapping variations (22)(23)(24)(25)(26)(27), and suggest an increased activation in both motor and paralimbic regions, and with altered fronto-striatal coupling among patients. One non-task, restingstate study, by Yao et al. (28) corroborates the hyperactivation of paralimbic regions in patients.

Electroencephalography
Electroencephalography (EEG) is used to study power amplitude of particular frequency spectrums, hemisphere asymmetry, and chronometric features of cortical neural activation. PMD have been associated with greater variability and increased amplitudes in the delta (<4 Hz) and theta (4-7 Hz) spectrum, but not with hemisphere asymmetry (29). The post-imperative negative variation is a metric related to frontal lobe function, and has been associated with psychomotor slowing in a choice reaction task (30). Another frontal metric (P300) has also been correlated positively correlated with PMD (31). Interestingly, this study also showed that only clinical ratings more focused on PMD than the Hamilton depression ratings scale (HDRS) predicted P300 latency. In a group of patients receiving electroconvulsive treatment, clinical ratings of PMD were positively correlated with frequency decreases during initial improvement, whereas the reverse relationship was found during the later partial remission phase (32). One study by Nieber et al. (33) showed a positive correlation between decreased frequencies in particular regions of the theta and alpha (7-13 Hz) spectrum and overall retardation, with motor retardation, in particular. In that study, increased frequency in particular regions of in the alpha and beta spectrum was negatively correlated with PMD. Errorrelated negativity and positive-negativity are metrics associated with anterior and posterior cingulate cortex function, respectively (34,35). These metrics have been associated with a slowing of psychomotor performance in subjects during action monitoring, but only positive-negativity differentiated patients and controls (36).

Molecular Neuroimaging
Single-photon emission tomography (SPECT), positron emission tomography (PET), and arterial spin labeling (ASL) are the three molecular neuroimaging methods that have been used to study PMD. These three methods measure regional cerebral blood flow, glucose metabolism, oxygen consumption, or synaptic transmission factors. Walther et al. (37) used ASL and actigraphy to measure the correlation between regional cerebral blood flow and general motor activity outside of the scanner environment in depressed subjects. The study showed a positive correlation between physical activity and blood perfusion in the right orbitofrontal cortex, and a negative correlation with left supplementary motor area perfusion. The available evidence from PET and SPECT studies also suggests that PMD in depression are associated with decreased DLPFC metabolism (38)(39)(40), increased ACC metabolism (41)(42)(43), and a lower dopaminergic tone and altered metabolism in striatal regions (41,42,(44)(45)(46)(47). However, a SPECT study by Graff-Guerrero et al. (48) failed to reproduce these associations between clinical rating of PMD and cerebral blood flow. One longitudinal study also suggests that improvement of psychomotor slowing is associated with increased activation in the dorsal ACC (49).

Transcranial Ultrasound
Hypo-or hyperechogenicity measured by transcranial sonography in vivo reflect changes in tissue impedance, likely due to alterations of microarchitecture such as shifts in cell density, changes in interstitial matrix composition, or alterations of fiber tract integrity (50,51). Those transcranial ultrasound studies that have investigated PMD in major depression have focused on the serotonergic raphe nuclei and the dopaminergic substantia nigrae. A significantly reduced echogenicity of the mesencephalic midline raphe nuclei has been reported in depressed subjects (52). Hypoechogenicity of the raphe nuclei can be found in 50-70% of unipolar depressed subjects compared to 10% in healthy subjects (53). Hypoechogenicity of the raphe nuclei of the brain stem is associated with better treatment response to serotonin reuptake inhibitors (54) and with symptom severity in suicidal ideation (55). One study could not find any association between echogenicity of the raphe nuclei and PMD (51), another found a positive correlation with the degree of psychomotor retardation (56), and a third a negative correlation with psychomotor retardation (54). Hoeppner et al. showed that substantia nigra echogenic size correlates with motor asymmetry and reduced verbal fluency in unipolar depression. In that study, the association was stronger in patients ≥50 years, and in patients with reduced brain stem raphe nuclei hypogenicity (57).

Conclusion
In this review, we summarize the literature on the functional neuroanatomy of PMD in major depressive disorder ( Table 2). Despite the clinical importance of PMD, we found relatively few studies. Indeed, the motor system has been relatively neglected in brain imaging studies of psychiatric disorders in general (58). We conclude that structural alterations that correlate with PMD have been found in gray-and white-matter regions within several nodes of cortico-subcortical circuits. Findings in functional neuroimaging studies show involvement of the same neurocircuitry nodes (along with their white-matter connections) as in structural neuroimaging studies, and further that limbic influences on the motor system may be important in the emergence of PMD. EEG studies suggest that frequency variations across many spectra, and an involvement of the frontal cortex, anterior, and posterior cingulate cortex, are associated with PMD. The molecular neuroimaging correlates of PMD resemble the functional anatomy of major depression described with functional and structural methods, but in addition also implicate disrupted monoamine transmission in PMD. The few available studies that use transcranial ultrasound primarily show an association between PMD and echogenic features of the substantia nigra, which then corroborates molecular neuroimaging findings of disrupted dopamine transmission.
Structural and functional neuroimaging studies suggest that PMD involve alterations in large-scale cortico-striato-thalamocortical neurocircuits, and in particular fronto-striatal subdivisions. Findings from transcranial ultrasound, and molecular neuroimaging studies, suggest a putative underlying factor for these alterations in the form of disrupted influence of ascending dopamine tracts that emanate from deeper midbrain nuclei. This notion also fits with the broader picture of a depressive disorder with psychomotor disturbances, which also include alterations in cognitive function, drive, and emotional expression -phenomena that also map onto ascending monoamine tracts with targets in the frontal lobe. Taken together, the broad picture suggests that PMD in major depressive disorder emerges from altered limbic signals at the interface of emotion, volition, higher-order cognitive function, and movement.
Our review shows that PMD is an emerging field of research that has kept growing since over 20 years. However, the currently available studies also preclude firmer evidence when evaluated  in the context of general research methodology. Most studies are cross-sectional, have <25 participants, and have not been reproduced. Furthermore, a wide variety of clinical psychomotor measures have been used. Thus, information about the anatomical specificity of PMD from future studies could be improved by the use of objective measurements of motor performance (i.e., fingertapping, actigraphy) when investigating the different dimensions of PMD delineated by current clinical measurements (i.e., CORE, MARS), and using rating scales that probe PMD specifically. Further studies would also benefit from longitudinal experimental designs that disentangle the effects of brain changes on the functional components of PMD, and assess differences across neuropsychiatric disorders.