Cognitive behavioural therapy for the treatment of late life depression: study protocol of a multicentre, randomized, observer-blinded, controlled trial (CBTlate).

BACKGROUND: Late-life depression (LLD) is one of the most prevalent mental disorders in old age. It is associated with various adverse outcomes and frequent use of health care services thereby remaining a serious public health concern. Compared with depression in early adulthood, most treatment options of LLD are less effective. Psychotherapy may be particularly beneficial for LLD due to specific psychological conditions in old age and a low risk of side effects. Although cognitive behavioural therapy (CBT) is highly established and effective in depression in young and mid-life there is only a limited number of small studies on CBT in LLD. An LLD-specific CBT has not yet been compared to an active, but unspecific supportive psychological intervention in a multicentre trial. METHODS: Here we present the design of the CBTlate trial, which is a multicentre, randomized, observer-blinded, active-controlled, parallel group trial. CBTlate aims at including 248 patients with LLD of both genders at 7 sites in Germany. The purpose of the study is to test the hypothesis that a 15-session individually-delivered CBT specific for LLD is of superior efficacy in reducing symptoms of depression in comparison with a supportive unspecific intervention (SUI) of the same quantity. The intervention includes 8 weeks of individual treatment sessions twice per week and a follow-up period of 6 months after randomization. The primary end point is the severity of depression at the end of treatment measured by the self-rated 30-item Geriatric Depression Scale (GDS). Secondary endpoints include depressive symptoms at week 5 and at follow-up (6 months after randomization). Additional secondary endpoints include the change of depressive symptoms assessed with a clinician-rating-scale and a patient reported outcome instrument for major depressive disorder, anxiety symptoms, sleep, cognition, quality of life, and overall health status from baseline to end-of treatment and to end of follow-up. Add-on protocols include MRI and the collection of blood samples. DISCUSSION: This study is the first multicentre trial of a specific CBT intervention for LLD compared to an unspecific supportive psychological intervention administered in a specialist setting. It has important implications for developing and implementing efficient psychotherapeutic strategies for LLD and may be a significant step to broaden treatment options for people suffering from LLD. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03735576, registered on 24 October 2018); DRKS (DRKS00013769, registered on 28 June 2018).

A transcallosal fibre system between homotopic inferior frontal regions supports complex linguistic processing.

Inferior frontal regions in the left and right hemisphere support different aspects of language processing. In the canonical model, left inferior frontal regions are mostly involved in processing based on phonological, syntactic and semantic features of language, whereas the right inferior frontal regions process paralinguistic aspects like affective prosody. Using diffusion tensor imaging (DTI)-based probabilistic fibre tracking in 20 healthy volunteers, we identify a callosal fibre system connecting left and right inferior frontal regions that are involved in linguistic processing of varying complexity. Anatomically, we show that the interhemispheric fibres are highly aligned and distributed along a rostral to caudal gradient in the body and genu of the corpus callosum to connect homotopic inferior frontal regions. In the light of converging data, taking previous DTI-based tracking studies and clinical case studies into account, our findings suggest that the right inferior frontal cortex not only processes paralinguistic aspects of language (such as affective prosody), as purported by the canonical model, but also supports the computation of linguistic aspects of varying complexity in the human brain. Our model may explain patterns of right-hemispheric contribution to stroke recovery as well as disorders of prosodic processing. Beyond language-related brain function, we discuss how inter-species differences in interhemispheric connectivity and fibre density, including the system we described here may also explain differences in transcallosal information transfer and cognitive abilities across different mammalian species.

The Dual-Loop Model and the Human Mirror Neuron System: an Exploratory Combined fMRI and DTI Study of the Inferior Frontal Gyrus.

The inferior frontal gyrus (IFG) is active during both goal-directed action and while observing the same motor act, leading to the idea that also the meaning of a motor act (action understanding) is represented in this "mirror neuron system" (MNS). However, in the dual-loop model, based on dorsal and ventral visual streams, the MNS is thought to be a function of the dorsal steam, projecting to pars opercularis (BA44) of IFG, while recent studies suggest that conceptual meaning and semantic analysis are a function of ventral connections, projecting mainly to pars triangularis (BA45) of IFG. To resolve this discrepancy, we investigated action observation (AO) and imitation (IMI) using fMRI in a large group of subjects. A grasping task (GR) assessed the contribution from movement without AO. We analyzed connections of the MNS-related areas within IFG with postrolandic areas with the use of activation-based DTI. We found that action observation with imitation are mainly a function of the dorsal stream centered on dorsal part of BA44, but also involve BA45, which is dorsally and ventrally connected to the same postrolandic regions. The current finding suggests that BA45 is the crucial part where the MNS and the dual-loop system interact.

The ventral fiber pathway for pantomime of object use.

The current concept of a dual loop system of brain organization predicts a domain-general dual-pathway architecture involving dorsal and ventral fiber connections. We investigated if a similar dichotomy of brain network organization applies for pantomime (P) and imitation of meaningless gestures (I). Impairments of these tasks occur after left hemispheric brain lesions causing apraxia. Isolated impairments and double-dissociations point towards an anatomical segregation. Frontal and parietal areas seem to contribute differently. A special role of the inferior frontal gyrus and underlying fiber pathways was suggested recently. Using a combined fMRI/DTI-approach, we compared the fiber pathway architecture of left hemispheric frontal, temporal and parietal network components of pantomime and imitation. Thereby, we separated object effects from pantomime-specific effects. P and I both engage a fronto-temporo-parietal network of cortical areas interconnected by a dorsal fiber system (superior longitudinal fascicle) for direct sensory-motor interactions. The pantomime-specific effect additionally involved the triangular part of the inferior frontal gyrus, the middle temporal gyrus, the inferior parietal cortex and the intraparietal sulcus, interconnected by ventral fibers of the extreme capsule, likely related to higher-order conceptual and semantic operations. We discuss this finding in the context of the dual loop model and recent anatomical concepts.

Neural bases of imitation and pantomime in acute stroke patients: distinct streams for praxis.

Apraxia is a cognitive disorder of skilled movements that characteristically affects the ability to imitate meaningless gestures, or to pantomime the use of tools. Despite substantial research, the neural underpinnings of imitation and pantomime have remained debated. An influential model states that higher motor functions are supported by different processing streams. A dorso-dorsal stream may mediate movements based on physical object properties, like reaching or grasping, whereas skilled tool use or pantomime rely on action representations stored within a ventro-dorsal stream. However, given variable results of past studies, the role of the two streams for imitation of meaningless gestures has remained uncertain, and the importance of the ventro-dorsal stream for pantomime of tool use has been questioned. To clarify the involvement of ventral and dorsal streams in imitation and pantomime, we performed voxel-based lesion-symptom mapping in a sample of 96 consecutive left-hemisphere stroke patients (mean age ± SD, 63.4 ± 14.8 years, 56 male). Patients were examined in the acute phase after ischaemic stroke (after a mean of 5.3, maximum 10 days) to avoid interference of brain reorganization with a reliable lesion-symptom mapping as best as possible. Patients were asked to imitate 20 meaningless hand and finger postures, and to pantomime the use of 14 common tools depicted as line drawings. Following the distinction between movement engrams and action semantics, pantomime errors were characterized as either movement or content errors, respectively. Whereas movement errors referred to incorrect spatio-temporal features of overall recognizable movements, content errors reflected an inability to associate tools with their prototypical actions. Both imitation and pantomime deficits were associated with lesions within the lateral occipitotemporal cortex, posterior inferior parietal lobule, posterior intraparietal sulcus and superior parietal lobule. However, the areas specifically related to the dorso-dorsal stream, i.e. posterior intraparietal sulcus and superior parietal lobule, were more strongly associated with imitation. Conversely, in contrast to imitation, pantomime deficits were associated with ventro-dorsal regions such as the supramarginal gyrus, as well as brain structures counted to the ventral stream, such as the extreme capsule. Ventral stream involvement was especially clear for content errors which were related to anterior temporal damage. However, movement errors were not consistently associated with a specific lesion location. In summary, our results indicate that imitation mainly relies on the dorso-dorsal stream for visuo-motor conversion and on-line movement control. Conversely, pantomime additionally requires ventro-dorsal and ventral streams for access to stored action engrams and retrieval of tool-action relationships.

Action semantics and movement characteristics engage distinct processing streams during the observation of tool use.

The cortical motor system follows a modular organization in which different features of executed movements are supported by distinct streams. Accordingly, different levels of action recognition, such as movement characteristics or action semantics may be processed within distinct networks. The present study aimed to differentiate areas related to the analysis of action features involving semantic knowledge from regions concerned with the evaluation of movement characteristics determined by structural object properties. To this end, the assessment of (i) tool-associated actions in relation to semantically, but not functionally inappropriate recipients (factor "Semantics"), and the evaluation of (ii) tool-associated movements performed with awkward versus correct hand postures (factor "Hand") were experimentally manipulated in an fMRI study with an event-related 2 × 2 factorial design. The videos used as stimuli displayed actions performed with the right hand in third-person perspective. Conjunction analysis of all four experimental conditions showed that observing videos depicting tool-related actions compared to rest was associated with widespread bilateral activity within the frontal lobes, inferior and superior parietal lobules, parts of the temporal lobes, as well as the occipital lobes. Viewing actions executed with incorrect compared to correct hand postures (factor "Hand") elicited significantly more activity within right primary sensory cortex (Brodmann area 2) and superior parietal lobule. Conversely, tool-associated actions displayed after semantically incorrect compared to correct recipients elicited higher activation within a left-lateralized network comprising the ventro-lateral prefrontal cortex (VLPFC), parts of the intraparietal sulcus and the angular gyrus (AG), as well as the supplementary motor area (SMA) and pre-SMA. Probabilistic diffusion tensor imaging-based tractography revealed two distinct fiber connections between AG and the frontal activation: A dorsal pathway via the superior longitudinal fascicle to the caudal part of VLPFC and a ventral pathway reaching the more rostral parts of VLPFC via the extreme capsule. The task-dependent relative modulation of activity within these brain networks composed of activated cortical areas connected by specific white matter tracts may indicate that the assessment of semantic action features relies on both dorso-ventral and ventral processing streams, whereas the analysis of hand postures with respect to objects depends on areas within the dorso-dorsal stream.

Ventral and dorsal fiber systems for imagined and executed movement.

Although motor imagery is an entirely cognitive process, it shows remarkable similarity to overt movement in behavioral and physiological studies. In concordance, brain imaging studies reported shared fronto-parietal sensorimotor networks commonly engaged by both tasks. However, differences in prefrontal and parietal regions point toward additional cognitive mechanisms in the context of imagery. Within the perspective of a general dichotomization into dorsal and ventral processing streams in the brain, the question arises whether motor imagery and overt movement could differentially involve the dorsal or ventral system. Therefore, we combined fMRI and DTI data of 20 healthy subjects to analyze the anatomical characteristics of connecting fronto-parietal association pathways of imagined and overt movements. We found a dichotomy of fiber pathways into dorsal and ventral systems: the superior longitudinal fascicle (SLF II-III) was found to connect frontal and parietal regions involved in both overt and imagined movements, whereas a ventral tract via the extreme/external capsule (EmC/EC) connects cortical regions specific for motor imagery that were situated more anteriorly and posteriorly. We suppose that motor imagery-related kinesthetic emulations are embedded into dorsal sensorimotor networks, and imagery-specific cognitive functions are implemented in the ventral system. These findings have implications for models of motor cognition.

Acute visual neglect and extinction: distinct functional state of the visuospatial attention system.

The neural mechanisms underlying spatial neglect are still disputed. Abnormal left parietal hyperactivation is proposed to lead to the rightward attentional bias, a clinical hallmark of neglect. Extinction, another deficit of visuospatial attention, is regarded as either a 'mild' form of neglect or a distinct syndrome. Although both neglect and extinction are typical syndromes of acute right hemispheric stroke, all imaging studies investigating these syndromes were conducted at least several weeks after stroke onset, in a phase when brain reorganization has already progressed. The present study aimed at comparing the activation patterns in acute stroke patients with neglect and extinction during visuospatial processing. Using functional magnetic resonance imaging, we examined the functional state of the attention system in 33 patients with a first ever stroke (53 ± 5 h after stroke onset) and age-matched healthy subjects (n = 15). All patients had embolic infarcts within the territory of the right middle cerebral artery. Patients were divided into three groups: (i) normal visuospatial processing (control patients, n = 11); (ii) patients with visual extinction but with no signs of neglect (n = 9); and (iii) patients with visual neglect (n = 13). While undergoing functional magnetic resonance imaging, patients performed a Posner-like task for visuospatial attention with detection of the targets in the left and right visual hemifields. Patients with neglect showed the expected imbalance in the left versus right parietal activation, which however, was present also in control and extinction patients, thus representing an epiphenomenon of the acute structural lesion in the right hemisphere. Compared with control patients, neglect was characterized by reduced activation in the right parietal and lateral occipital cortex, as well as in the left frontal eye field. In contrast, the activation pattern in patients with extinction differed from all other groups by an increased activation of the left prefrontal cortex. In both patients with neglect and extinction, detection of targets in the left hemifield correlated with an activation in the left prefrontal and parietal cortex. Thus at least in acute stroke, a relative hyperactivation of the left parietal cortex is not a particular characteristic of neglect. The specific signature of neglect is represented by the dysfunction of the right parietal and lateral occipital cortex. The function of the left attentional centres might provide a compensatory role after critical right hemisphere lesions and be relevant for the contralesional spatial processing.

Prediction of motor recovery using initial impairment and fMRI 48 h poststroke.

There is substantial interpatient variation in recovery from upper limb impairment after stroke in patients with severe initial impairment. Defining recovery as a change in the upper limb Fugl-Meyer score (ΔFM), we predicted ΔFM with its conditional expectation (i.e., posterior mean) given upper limb Fugl-Meyer initial impairment (FM(ii)) and a putative functional magnetic resonance imaging (fMRI) recovery measure. Patients with first time, ischemic stroke were imaged at 2.5 ± 2.2 days poststroke with 1.5-T fMRI during a hand closure task alternating with rest (fundamental frequency = 0.025 Hz, scan duration = 172 s). Confirming a previous finding, we observed that the prediction of ΔFM by FM(ii) alone is good in patients with nonsevere initial hemiparesis but is not good in patients with severe initial hemiparesis (96% and 16% of the total sum of squares of ΔFM explained, respectively). In patients with severe initial hemiparesis, prediction of ΔFM by the combination of FM(ii) and the putative fMRI recovery measure nonsignificantly increased predictive explanation from 16% to 47% of the total sum of squares of ΔFM explained. The implications of this preliminary negative result are discussed.

Structural connectivity for visuospatial attention: significance of ventral pathways.

In the present study, we identified the most probable trajectories of point-to-point segregated connections between functional attentional centers using a combination of functional magnetic resonance imaging and a novel diffusion tensor imaging-based algorithm for pathway extraction. Cortical regions activated by a visuospatial attention task were subsequently used as seeds for probabilistic fiber tracking in 26 healthy subjects. Combining probability maps of frontal and temporoparietal regions yielded a network that consisted of dorsal and ventral connections. The dorsal connections linked temporoparietal cortex with the frontal eye field and area 44 of the inferior frontal gyrus (IFG). Traveling along superior longitudinal and arcuate fascicles, these fibers are well described in relation to spatial attention. However, the ventral connections, which traveled in the white matter between insula (INS) cortex and putamen parallel to the sylvian fissure, were not previously described for visuospatial attention. Linking temporoparietal cortex with anterior INS and area 45 of IFG, these connections may provide an anatomical substrate for crossmodal cortical integration needed for stimulus perception and response in relation to current intention. The newly anatomically described integral network for visuospatial attention might improve the understanding of spatial attention deficits after white matter lesions.

The longitudinal changes of BOLD response and cerebral hemodynamics from acute to subacute stroke. A fMRI and TCD study.

BACKGROUND: By mapping the dynamics of brain reorganization, functional magnetic resonance imaging MRI (fMRI) has allowed for significant progress in understanding cerebral plasticity phenomena after a stroke. However, cerebro-vascular diseases can affect blood oxygen level dependent (BOLD) signal. Cerebral autoregulation is a primary function of cerebral hemodynamics, which allows to maintain a relatively constant blood flow despite changes in arterial blood pressure and perfusion pressure. Cerebral autoregulation is reported to become less effective in the early phases post-stroke. This study investigated whether any impairment of cerebral hemodynamics that occurs during the acute and the subacute phases of ischemic stroke is related to changes in BOLD response. We enrolled six aphasic patients affected by acute stroke. All patients underwent a Transcranial Doppler to assess cerebral autoregulation (Mx index) and fMRI to evaluate the amplitude and the peak latency (time to peak-TTP) of BOLD response in the acute (i.e., within four days of stroke occurrence) and the subacute (i.e., between five and twelve days after stroke onset) stroke phases. RESULTS: As patients advanced from the acute to subacute stroke phase, the affected hemisphere presented a BOLD TTP increase (p = 0.04) and a deterioration of cerebral autoregulation (Mx index increase, p = 0.046). A similar but not significant trend was observed also in the unaffected hemisphere. When the two hemispheres were grouped together, BOLD TTP delay was significantly related to worsening cerebral autoregulation (Mx index increase) (Spearman's rho = 0.734; p = 0.01). CONCLUSIONS: The hemodynamic response function subtending BOLD signal may present a delay in peak latency that arises as patients advance from the acute to the subacute stroke phase. This delay is related to the deterioration of cerebral hemodynamics. These findings suggest that remodeling the fMRI hemodynamic response function in the different phases of stroke may optimize the detection of BOLD signal changes.

Ventral and dorsal pathways for language.

Built on an analogy between the visual and auditory systems, the following dual stream model for language processing was suggested recently: a dorsal stream is involved in mapping sound to articulation, and a ventral stream in mapping sound to meaning. The goal of the study presented here was to test the neuroanatomical basis of this model. Combining functional magnetic resonance imaging (fMRI) with a novel diffusion tensor imaging (DTI)-based tractography method we were able to identify the most probable anatomical pathways connecting brain regions activated during two prototypical language tasks. Sublexical repetition of speech is subserved by a dorsal pathway, connecting the superior temporal lobe and premotor cortices in the frontal lobe via the arcuate and superior longitudinal fascicle. In contrast, higher-level language comprehension is mediated by a ventral pathway connecting the middle temporal lobe and the ventrolateral prefrontal cortex via the extreme capsule. Thus, according to our findings, the function of the dorsal route, traditionally considered to be the major language pathway, is mainly restricted to sensory-motor mapping of sound to articulation, whereas linguistic processing of sound to meaning requires temporofrontal interaction transmitted via the ventral route.