Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques.

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network.

Functional reorganization during the recovery of contralesional target selection deficits after prefrontal cortex lesions in macaque monkeys.

Visual extinction has been characterized by the failure to respond to a visual stimulus in the contralesional hemifield when presented simultaneously with an ipsilesional stimulus (Corbetta and Shulman, 2011). Unilateral damage to the macaque frontoparietal cortex commonly leads to deficits in contralesional target selection that resemble visual extinction. Recently, we showed that macaque monkeys with unilateral lesions in the caudal prefrontal cortex (PFC) exhibited contralesional target selection deficits that recovered over 2-4 months (Adam et al., 2019). Here, we investigated the longitudinal changes in functional connectivity (FC) of the frontoparietal network after a small or large right caudal PFC lesion in four macaque monkeys. We collected ultra-high field resting-state fMRI at 7-T before the lesion and at weeks 1-16 post-lesion and compared the functional data with behavioural performance on a free-choice saccade task. We found that the pattern of frontoparietal network FC changes depended on lesion size, such that the recovery of contralesional extinction was associated with an initial increase in network FC that returned to baseline in the two small lesion monkeys, whereas FC continued to increase throughout recovery in the two monkeys with a larger lesion. We also found that the FC between contralesional dorsolateral PFC and ipsilesional parietal cortex correlated with behavioural recovery and that the contralesional dorsolateral PFC showed increasing degree centrality with the frontoparietal network. These findings suggest that both the contralesional and ipsilesional hemispheres play an important role in the recovery of function. Importantly, optimal compensation after large PFC lesions may require greater recruitment of distant and intact areas of the frontoparietal network, whereas recovery from smaller lesions was supported by a normalization of the functional network.

Recovery of contralesional saccade choice and reaction time deficits after a unilateral endothelin-1-induced lesion in the macaque caudal prefrontal cortex.

The caudal primate prefrontal cortex (PFC) is involved in target selection and visually guided saccades through both covert attention and overt orienting eye movements. Unilateral damage to the caudal PFC often leads to decreased awareness of a contralesional target alone, referred to as "neglect," or when it is presented simultaneously with an ipsilesional target, referred to as "extinction." In the current study, we examined whether deficits in contralesional target selection were due to contralesional oculomotor deficits, such as slower reaction times. We experimentally induced a focal ischemic lesion in the right caudal PFC of 4 male macaque monkeys using the vasoconstrictor endothelin-1 and measured saccade choice and reaction times on double-stimulus free-choice tasks and single-stimulus trials before and after the lesion. We found that 1) endothelin-1-induced lesions in the caudal PFC produced contralesional target selection deficits that varied in severity and duration based on lesion volume and location; 2) contralesional neglect-like deficits were transient and recovered by week 4 postlesion; 3) contralesional extinction-like deficits were longer lasting and recovered by weeks 8-16 postlesion; 4) contralesional reaction time returned to baseline well before the contralesional choice deficit had recovered; and 5) neither the mean reaction times nor the reaction time distributions could account for the degree of contralesional extinction on the free-choice task throughout recovery. These findings demonstrate that the saccade choice bias observed after a right caudal PFC lesion is not exclusively due to contralesional motor deficits, but instead reflects a combination of impaired motor and attentional processing.NEW & NOTEWORTHY Unilateral damage to the caudal prefrontal cortex in macaque monkeys results in impaired contralesional target selection during the simultaneous presentation of an ipsilesional target. We show that the recovery of contralesional target selection cannot be explained by the recovery of prolonged contralesional saccadic reaction times alone. This indicates that an impairment in contralesional attentional processing contributes to the magnitude of the saccade choice bias in the weeks following a unilateral caudal prefrontal cortex lesion.

Diffusion-weighted tractography in the common marmoset monkey at 9.4T.

The common marmoset (Callithrix jacchus) is a small New World primate that is becoming increasingly popular in the neurosciences as an animal model of preclinical human disease. With several major disorders characterized by alterations in neural white matter (e.g., multiple sclerosis, Alzheimer's disease, schizophrenia), proposed to be transgenically modeled using marmosets, the ability to isolate and characterize reliably major white matter fiber tracts with MRI will be of use for evaluating structural brain changes related to disease processes and symptomatology. Here, we propose protocols for isolating major white matter fiber tracts in the common marmoset using in vivo ultrahigh-field MRI (9.4T) diffusion-weighted imaging (DWI) data. With the use of a high angular-resolution DWI (256 diffusion-encoding directions) sequence, collected on four anesthetized marmosets, we provide guidelines for manually drawing fiber-tracking regions of interest, based on easily identified anatomical landmarks in DWI native space. These fiber-tract isolation protocols are expected to be experimentally useful for visualization and quantification of individual white matter fiber tracts in both control and experimental groups of marmosets (e.g., transgenic models). As disease models in the marmoset advance, the determination of how macroscopic white matter anatomy is altered as a function of disease state will be relevant in bridging the existing translational gap between preclinical rodent models and human patients.NEW & NOTEWORTHY Although significant progress has been made in mapping white matter connections in the marmoset brain using ex vivo tracing techniques, the application of in vivo virtual dissection of major white matter fiber tracts has been established by few studies in the marmoset literature. Here, we demonstrate the feasibility of whole-brain diffusion-weighted tractography in anesthetized marmosets at ultrahigh-field MRI (9.4T) and propose protocols for isolating nine major white matter fiber tracts in the marmoset brain.

Insight into motor control and motor impairment from stroke and beta oscillations.

Beta oscillations are associated with motor function and are thought to play a role in movement impairment. In a recent magnetoencephalography (MEG) study, Rossiter et al. (J Neurophysiol 112: 2053-2058, 2014) found a disruption in the modulation of movement-related beta oscillations in stroke patients that correlated with motor impairment. We discuss how beta oscillatory measures characterize motor impairment, the implications of stroke variability, and the potential role of GABA in modulating oscillations following stroke and during stroke recovery.

Brain Network Connectivity and Executive Function in Children with Infantile Hydrocephalus.

Introduction: Infantile hydrocephalus (HCP) is a condition in which there is an abnormal buildup of cerebrospinal fluid in the ventricles within the first few months of life, which puts pressure on surrounding brain tissues. Compression of the developing brain increases the risk of secondary brain injury and cognitive disabilities. Methods: In this study, we used diffusion-weighted imaging and resting-state functional magnetic resonance imaging to investigate the effects of ventricle dilatation on structural and functional brain networks in children with shunted infantile HCP and examined how these brain changes may impact executive function. Results: We found that children with HCP have altered structural and functional connectivity between and within large-scale networks. Moreover, hyperconnectivity between the ventral attention and default mode network in children with HCP correlated with reduced executive function scores. Compared with typically developing age-matched control participants, our patient population also had lower fractional anisotropy in posterior white matter. Discussion: Overall, these findings suggest that infantile HCP has long-term effects on brain network connectivity, white matter development, and executive function in children at school age. Future work will examine the relationship between ventricular volumes before shunt placement in infancy and brain network development throughout childhood.

Shared functional connectivity between the dorso-medial and dorso-ventral streams in macaques.

Manipulation of an object requires us to transport our hand towards the object (reach) and close our digits around that object (grasp). In current models, reach-related information is propagated in the dorso-medial stream from posterior parietal area V6A to medial intraparietal area, dorsal premotor cortex, and primary motor cortex. Grasp-related information is processed in the dorso-ventral stream from the anterior intraparietal area to ventral premotor cortex and the hand area of primary motor cortex. However, recent studies have cast doubt on the validity of this separation in separate processing streams. We investigated in 10 male rhesus macaques the whole-brain functional connectivity of these areas using resting state fMRI at 7-T. Although we found a clear separation between dorso-medial and dorso-ventral network connectivity in support of the two-stream hypothesis, we also found evidence of shared connectivity between these networks. The dorso-ventral network was distinctly correlated with high-order somatosensory areas and feeding related areas, whereas the dorso-medial network with visual areas and trunk/hindlimb motor areas. Shared connectivity was found in the superior frontal and precentral gyrus, central sulcus, intraparietal sulcus, precuneus, and insular cortex. These results suggest that while sensorimotor processing streams are functionally separated, they can access information through shared areas.