Increased hippocampal-inferior temporal cortex white matter connectivity following donepezil treatment in patients with mild cognitive impairment: A diffusion tensor probabilistic tractography study

The incidence of Alzheimer’s disease (AD) has been increasing each year; however, few methods are available to identify the effects of treatment for AD. Defective hippocampus has been associated with mild cognitive impairment (MCI), an early stage of AD. However, the effect of donepezil treatment on hippocampus-related networks is unknown. The purpose of this study was to evaluate the hippocampal white matter (WM) connectivity following donepezil treatment in patients with MCI using probabilistic tractography, and to further determine the WM integrity and changes in brain volume. Magnetic resonance imaging and diffusion tensor imaging (DTI) data of patients with MCI before and after 6-month donepezil treatment were acquired. Volumes and DTI scalars of 11 regions of interest comprising the frontal and temporal cortices and subcortical regions were measured. Seed-based structural connectivity analyses were focused on the hippocampus. Compared with healthy controls, patients with MCI showed significantly decreased hippocampal volume and WM connectivity with the superior frontal gyrus, as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the amygdala (p < 0.05, Bonferroni-corrected). After six months of donepezil treatment, patients with MCI showed increased hippocampal-inferior temporal gyrus (ITG) WM connectivity (p < 0.05, Bonferroni-corrected), which was normalized to the healthy control. These findings will be useful in developing theories to describe the etiology of MCI and the therapeutic role of anticholinesterases.

Use of probabilistic tractography to provide reliable distinction of the motor and sensory thalamus for prospective targeting during asleep deep brain stimulation

OBJECTIVE Accurate electrode placement is key to effective deep brain stimulation (DBS). The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for the treatment of essential tremor (ET). Retrospective tractography-based analysis of electrode placement has associated successful outcomes with modulation of motor input to VIM, but no study has yet evaluated the feasibility and efficacy of prospective presurgical tractography-based targeting alone. Therefore, the authors sought to demonstrate the safety and efficacy of probabilistic tractography–based VIM targeting in ET patients and to perform a systematic comparison of probabilistic and deterministic tractography. METHODS Fourteen patients with ET underwent preoperative diffusion imaging. Probabilistic tractography was applied for preoperative targeting, and deterministic tractography was performed as a comparison between methods. Tractography was performed using the motor and sensory areas as initiation seeds, the ipsilateral thalamus as an inclusion mask, and the contralateral dentate nucleus as a termination mask. Tract-density maps consisted of voxels with 10% or less of the maximum intensity and were superimposed onto anatomical images for presurgical planning. Target planning was based on probabilistic tract-density images and indirect target coordinates. Patients underwent robotic image-guided, image-verified implantation of directional DBS systems. Postoperative tremor scores with and without DBS were recorded. The center of gravity and Dice similarity coefficients were calculated and compared between tracking methods. RESULTS Prospective probabilistic targeting of VIM was successful in all 14 patients. All patients experienced significant tremor reduction. Formal postoperative tremor scores were available for 9 patients, who demonstrated a mean 68.0% tremor reduction. Large differences between tracking methods were observed across patients. Probabilistic tractography–identified VIM fibers were more anterior, lateral, and superior than deterministic tractography–identified fibers, whereas probabilistic tractography–identified ventralis caudalis fibers were more posterior, lateral, and superior than deterministic tractography–identified fibers. Deterministic methods were unable to clearly distinguish between motor and sensory fibers in the majority of patients, but probabilistic methods produced distinct separation. CONCLUSIONS Probabilistic tractography–based VIM targeting is safe and effective for the treatment of ET. Probabilistic tractography is more precise than deterministic tractography for the delineation of VIM and the ventralis caudalis nucleus of the thalamus. Deterministic algorithms tended to underestimate separation between motor and sensory fibers, which may have been due to its limitations with crossing fibers. Larger studies across multiple centers are necessary to further validate this method.

Connectome-Based Smoothing (CBS): Concepts, methods, and evaluation

Structural connectomes are increasingly mapped at high spatial resolutions comprising many hundreds—if not thousands—of network nodes. However, high-resolution connectomes are particularly susceptible to image registration misalignment, tractography artifacts, and noise, all of which can lead to reductions in connectome accuracy and test-retest reliability. We investigate a network analogue of image smoothing to address these key challenges. Connectome-Based Smoothing (CBS) involves jointly applying a carefully chosen smoothing kernel to the two endpoints of each tractography streamline, yielding a spatially smoothed connectivity matrix. We develop computationally efficient methods to perform CBS using a matrix congruence transformation and evaluate a range of different smoothing kernel choices on CBS performance. We find that smoothing substantially improves the identifiability, sensitivity, and test-retest reliability of high-resolution connectivity maps, though at a cost of increasing storage burden. For atlas-based connectomes (i.e. low-resolution connectivity maps), we show that CBS marginally improves the statistical power to detect associations between connectivity and cognitive performance, particularly for connectomes mapped using probabilistic tractography. CBS was also found to enable more reliable statistical inference compared to connectomes without any smoothing. We provide recommendations on optimal smoothing kernel parameters for connectomes mapped using both deterministic and probabilistic tractography. We conclude that spatial smoothing is particularly important for the reliability of high-resolution connectomes, but can also provide benefits at lower parcellation resolutions. We hope that our work enables computationally efficient integration of spatial smoothing into established structural connectome mapping pipelines.

Temporo-cerebellar connectivity underlies timing constraints in audition

The flexible and efficient adaptation to dynamic, rapid changes in the auditory environment likely involves generating and updating of internal models. Such models arguably exploit connections between the neocortex and the cerebellum, supporting proactive adaptation. Here we tested whether temporo-cerebellar disconnection is associated with the processing of sound at short-timescales. First, we identify lesion-specific deficits for the encoding of short timescale spectro-temporal non-speech and speech properties in patients with left posterior temporal cortex stroke. Second, using lesion- guided probabilistic tractography in healthy participants, we revealed bidirectional temporo-cerebellar connectivity with cerebellar dentate nuclei and crura I/II. These findings support the view that the encoding and modeling of rapidly modulated auditory spectro-temporal properties can rely on a temporo-cerebellar interface. We discuss these findings in view of the conjecture that proactive adaptation to a dynamic environment via internal models is a generalizable principle.

Unilateral Blinking: Insights from Stereo-EEG and Tractography

To study the neuroanatomical correlate of involuntary unilateral blinking in humans, using the example of patients with focal epilepsy. Patients with drug resistant focal epilepsy undergoing presurgical evaluation with stereotactically implanted EEG-electrodes (sEEG) were recruited from the local epilepsy monitoring unit. Only patients showing ictal unilateral blinking or unilateral blinking elicited by direct electrical stimulation were included (n = 16). MRI and CT data were used for visualization of the electrode positions. In two patients, probabilistic tractography with seeding from the respective electrodes was additionally performed. Three main findings were made: (1) involuntary unilateral blinking was associated with activation of the anterior temporal region, (2) tractography showed widespread projections to the ipsilateral frontal, pericentral, occipital, limbic and cerebellar regions and (3) blinking was observed predominantly in female patients with temporal lobe epilepsies. Unilateral blinking was found to be associated with an ipsilateral activation of the anterior temporal region. We suggest that the identified network is not part of the primary blinking control but might have modulating influence on ipsilateral blinking by integrating contextual information.

Structural brain connectivity in children with developmental dyscalculia

Developmental dyscalculia (DD) is a neurodevelopmental disorder specific to arithmetic learning even with normal intelligence and age-appropriate education. Difficulties often persist from childhood through adulthood. Underlying neurobiological mechanisms of DD, however, are poorly understood. This study aimed to identify possible structural connectivity alterations in DD. We evaluated 10 children with pure DD (11.3 plus-or-minus sign 0.7 years) and 16 typically developing (TD) peers (11.2 plus-or-minus sign 0.6 years) using diffusion tensor imaging. We first assessed white matter microstructure with tract-based spatial statistics. Then we used probabilistic tractography to evaluate tract lengths and probabilistic connectivity maps in specific regions. At whole brain level, we found no significant microstructural differences in white matter between children with DD and TD peers. Also, seed-based connectivity probabilities did not differ between groups. However, we did find significant differences in regions-of-interest tracts which had previously been related to math ability in children. The major findings of our study were reduced white matter coherence and shorter tract lengths of the left superior longitudinal/arcuate fasciculus and left anterior thalamic radiation in the DD group. Furthermore, lower white matter coherence and shorter pathways corresponded with the lower math performance as a result of the correlation analyses. These results from regional analyses indicate that learning, memory and language-related pathways in the left hemisphere might underlie DD. Keywords: Mathematical learning disability, diffusion tensor imaging, superior longitudinal fasciculus, anterior thalamic radiation, probabilistic tractography, tract-based spatial statistics