Fahad Sultan

The effects of electrical microstimulation on cortical signal propagation

Electrical stimulation has been used in animals and humans to study potential causal links between neural activity and specific cognitive functions. Recently, it has found increasing use in electrotherapy and neural prostheses. However, the manner in which electrical stimulation–elicited signals propagate in brain tissues remains unclear. We used combined electrostimulation, neurophysiology, microinjection and functional magnetic resonance imaging (fMRI) to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We found that stimulation of a site in the lateral geniculate nucleus (LGN) increased the fMRI signal in the regions of primary visual cortex (V1) that received input from that site, but suppressed it in the retinotopically matched regions of extrastriate cortex. Consistent with previous observations, intracranial recordings indicated that a short excitatory response occurring immediately after a stimulation pulse was followed by a long-lasting inhibition. Following microinjections of GABA antagonists in V1, LGN stimulation induced positive fMRI signals in all of the cortical areas. Taken together, our findings suggest that electrical stimulation disrupts cortico-cortical signal propagation by silencing the output of any neocortical area whose afferents are electrically stimulated.

Mapping Cortical Activity Elicited with Electrical Microstimulation Using fMRI in the Macaque

Over the last two centuries, electrical microstimulation has been used to demonstrate causal links between neural activity and specific behaviors and cognitive functions. However, to establish these links it is imperative to characterize the cortical activity patterns that are elicited by stimulation locally around the electrode and in other functionally connected areas. We have developed a technique to record brain activity using the blood oxygen level dependent (BOLD) signal while applying electrical microstimulation to the primate brain. We find that the spread of activity around the electrode tip in macaque area V1 was larger than expected from calculations based on passive spread of current and therefore may reflect functional spread by way of horizontal connections. Consistent with this functional transynaptic spread we also obtained activation in expected projection sites in extrastriate visual areas, demonstrating the utility of our technique in uncovering in vivo functional connectivity maps.

FUNCTIONAL LOCALIZATION IN THE CEREBELLUM

In this paper we review the basic anatomy and functional localization in the cerebellum. Experimental anatomical studies emphasize the predominance of skeletomotor and visuomotor connections. Parietal lobe visual inputs arise principally from the dorsal stream extrastriate visual areas, which are specialized for the visual control of movement. There are few or no inputs to the cerebellum from inferotemporal cortex. Much of the input from prefrontal cortex is from areas that control eye movements. Comparative anatomical studies of the hominoid dentate nucleus are consistent with the role of much of the cerebellar hemispheres in the visual guidance of movement. Although some mossy and climbing fibre afferents to the cerebellum are reciprocally organized, feeding back onto their original source, the reciprocity does not exist for the visuomotor division. The dorsal paraflocculus receives its mossy fibres from extrastriate areas of the dorsal visual stream, and projects to the frontal eye fields. Functional magnetic resonance imaging (fMRI) studies in human subjects confirm the presence of somatotopically organized anterior and posterior skeletomotor areas with eye movement activity centred in the oculomotor vermis. Oculomotor and skeletomotor representation extend into adjacent Crus I and II. Discrepancies between the results of imaging studies in human subjects and experimental data are discussed. Skeletomotor activity or eye movements may contaminate many fMRI studies of putative cognitive functions of the cerebellum.

The Cerebellum at Birth in Therian Mammals, with Special Reference to Rodents

The stage of cerebellar development at birth was assessed in 23 species of placental mammals. Serial histological sections were examined and five stages in the differentiation of the cerebellar cortical layers were defined. A wide diversity of conditions at birth was found. The available evidence (after parsimony reconstruction) suggests that the last common ancestor of placentals was born with an altricial cerebellum in which the molecular layer was just present between the external granular layer and the prospective Purkinje cell layer. Some placental species have an even more altricial cerebellum at birth (e.g., Muscardinus avellanarius, Sorex araneus), with Mesocricetus auratus as the most altricial species among the taxa studied. In the newborn M. auratus a cerebellar anlage was present with only a loose accumulation of cells located at the dorsal cerebellar anlage above the ventricular neuroepithelial layer. The five species of caviomorph rodents examined here are relatively precocial as far as the cerebellum is concerned. The only other rodent species that has a similarly advanced state was the murid Acomys sp. Most of the life history variables examined were not strongly correlated with the cerebellar stage at birth if at all. However, a significant positive correlation (r2 = 0.67) was observed between the cerebellar stage at birth and the gestation length and a significant negative correlation (r2 = 0.31) was observed between cerebellar stage and the average litter size. The weak correlation may be due to sampling among different distantly related clades. The most mature cerebella at birth still had an external granular layer, indicating that the mossy fiber-granule cell connectivity is not yet fully developed and further indicating that this connectivity may depend on external experience to fully mature. All species that have their eyes open at birth also have the most mature cerebelli. The growth of the cortical layers was also studied in a postnatal ontogenetic series of the marsupial Monodelphis domestica. As is the case with placentals, the most advanced stage of cerebellar development coincides with the opening of the eyes.

Unravelling cerebellar pathways with high temporal precision targeting motor and extensive sensory and parietal networks

Increasing evidence has implicated the cerebellum in providing forward models of motor plants predicting the sensory consequences of actions. Assuming that cerebellar input to the cerebral cortex contributes to the cerebro-cortical processing by adding forward model signals, we would expect to find projections emphasising motor and sensory cortical areas. However, this expectation is only partially met by studies of cerebello-cerebral connections. Here we show that by electrically stimulating the cerebellar output and imaging responses with functional magnetic resonance imaging, evoked blood oxygen level-dependant activity is observed not only in the classical cerebellar projection target, the primary motor cortex, but also in a number of additional areas in insular, parietal and occipital cortex, including sensory cortical representations. Further probing of the responses reveals a projection system that has been optimized to mediate fast and temporarily precise information. In conclusion, both the topography of the stimulation effects and its emphasis on temporal precision are in full accordance with the concept of cerebellar forward model information modulating cerebro-cortical processing.

Why some bird brains are larger than others

How does brain size and design influence the survival chances of a species? A large brain may contribute to an individual’s success irrespective of its detailed composition. I have studied the size and shape of cerebella in birds and looked for links between the bird’s cerebellar design, brain size and behavior. My results indicate that the cerebellum in large-brained birds does not scale uniformly, but occurs in two designs. Crows, parrots and woodpeckers show an enlargement of the cerebellar trigeminal and visual parts, while owls show an enlargement of vestibular and tail somatosensory cerebellar regions, likely related to their specialization as nocturnal raptors.

Neurochemical and Structural Organization of the Principal Nucleus of the Inferior Olive in the Human

The inferior olive (IO) is the sole source of the climbing fibers that innervate the Purkinje cells of the cerebellar cortex. The IO comprises several subdivisions, the dorsal accessory olive (DAO), medial accessory olive (MAO), and principal nuclei of the IO (IOpr); the relative sizes of these subnuclei vary among species. In human, there is an expansion of the cerebellar hemispheres and a corresponding expansion of the IOpr. We have examined the structural and neurochemical organization of the human IOpr, using sections stained with cresyl violet (CV) or immunostained for the calcium‐binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV), the synthetic enzyme for nitric oxide (nNOS), and nonphosphorylated neurofilament protein (NPNFP). We found qualitative differences in the folding patterns of the IOpr among individuals and between the two sides of the brainstem. Quantification of IOpr volumes and indices of folding complexity, however, did not reveal consistent left–right differences in either parameter. Single‐label immunohistochemistry showed that populations of neurons in the IOpr express CB, CR, NPNFP, and nNOS. Individual fibers labeled for PV, CB, CR, NPNFP, and nNOS were also found. There was individual variability in the numbers and density of stained neurons in the human IOpr; such variability was not seen in other brainstem nuclei. These data are consistent with, and complement, earlier studies showing a dramatic age‐related increase in lipofuscin and decrease in RNA in the human IOpr. The impact of these changes in the IOpr on cerebellar function is, however, not known. Anat Rec,, 2011.

esfMRI of the upper STS: further evidence for the lack of electrically induced polysynaptic propagation of activity in the neocortex

Combining electrical stimulation with fMRI (esfMRI) has proven to be an important tool to study the global effects of electrical stimulation on neural networks in the brain. Here we extend our previous studies to stimulating the upper superior temporal sulcus (STS) in the anesthetized monkey. Our results show that stimulating area V5/MT and surrounding areas leads to positive BOLD responses in the majority of cortical areas known to receive direct/monosynaptic connections from the stimulation site. We confirm our previous results from stimulating primary visual cortex that the propagation of electrically induced activity is limited in its transsynaptic propagation to the first synapse also for extrastriate areas.

Flat map areal topography in Macaca mulatta based on combined MRI and histology

Flattened representations are a useful approach to represent the convoluted complex surface of the neocortex of primates and other large-brained mammals. In this study, we compared the flattened representation of neocortical areas obtained from the recently published MRI and histology atlas of the rhesus monkey brain (Saleem KS, Logothetis NK. A combined MRI and histology atlas of the rhesus monkey brain in stereotaxic coordinates. London: Academic; 2007) with other previously published maps. Our results confirm that flat map representations are advantageous due to their ease of use and that current flat maps are well comparable to each other. Some differences arise due to different distinguishing criteria and here too flat maps can help to reveal them.

Post-cueing deficits with maintained cueing benefits in patients with Parkinson's disease dementia

In Parkinson’s disease (PD), internal cueing mechanisms are impaired leading to symptoms like hypokinesia. However, external cues can improve movement execution by using cortical resources. These cortical processes can be affected by cognitive decline in dementia. It is still unclear how dementia in PD influences external cueing. We investigated a group of 25 PD patients with dementia (PDD) and 25 non-demented PD patients (PDnD) matched by age, sex, and disease duration in a simple reaction time task using an additional acoustic cue. PDD patients benefited from the additional cue in similar magnitude as did PDnD patients. However, withdrawal of the cue led to a significantly increased reaction time in the PDD group compared to the PDnD patients. Our results indicate that even PDD patients can benefit from strategies using external cue presentation but the process of cognitive worsening can reduce the effect when cues are withdrawn.