Neuronal activity of human caudate nucleus and prefrontal cortex in cognitive tasks

Abstract

Lesions of the caudate nucleus and prefrontal cortex may display similar cognitive deficits. Recent advances in cognitive neuroscience have clarified the functional role of prefrontal cortical areas in certain cognitive operations involved in simple language tasks. We have addressed the role of the caudate nucleus in tasks of lexical decision, semantic categorization, recognition memory, reading aloud and object naming by recording neuronal activity in patients with depth electrodes. During visual processing of words, caudate cells exhibited excitatory responses related to both semantic and phonological-articulatory encoding with non-overlapping time courses. The firing rate of the cells was increased when the semantic processing was required. This occurred within 400–600 ms after the stimulus onset, or within the first 200–300 ms of the delay period. The increased firing within 1000–1200 ms after the stimulus onset was related to the phonological processing. These responses turned out to be strikingly similar to those in Broca’s area. Both reading aloud and explicit memory retrieval tasks elicited a sustained inhibition of firing of the same cells with a greater onset latency. Chronometric comparison of prefrontal, temporo-parietal and caudate activities in similar tasks relates the time course of these activations to the fronto-caudate anatomical loops and helps further understanding of the anatomy and circuitry involved in human cognition.

Introduction

The caudate nuclei are symmetrical nuclei in the left and right subcortical regions of the brain considered anatomically as a part of basal ganglia. Functions of the basal ganglia were classically associated with various aspects of motor control. Recent reviews illustrate considerable functional distinctions among different regions of basal ganglia 6, 32, 46, each region receiving input from several functionally related cortical areas.

There are several reasons to believe that the head of the caudate nucleus seems to function similarly to the prefrontal cortex and may share with prefrontal regions a relation to certain cognitive functions. Prefrontal lesions acquired during prenatal development result in a bilateral increase of the caudate nuclei in volume with normal neuronal density [75]. Although dopaminergic innervation is widely distributed in the human neocortex [39], major accumulations of dopamine in the human brain demonstrated by positron emission tomography (PET) are in striatum, lateral frontal cortex and anterior cingulate [54]. Recent successes in voltammetric in vivo recording of neurotransmitter levels in different brain regions of behaving animals have demonstrated that the dopamine release in frontal cortex and in striatum may be correlated [90]. Depletion of dopamine in the prefrontal cortex has the same effect on delayed alternation performance in non-human primates as do lesions and this effect is reversible by dopamine agonists [24]. Experimental lesions of the anterior dorsolateral frontal cortex and the caudate nucleus in monkeys may produce strikingly similar behavioral deficits in delayed alternation and delayed response tasks leaving performance on simple visual discrimination tasks unaffected 12, 43, 108. The caudate nucleus receives a visual input with early onset latency 28, 65, 68, 69, 107which appears important for memory functions 66, 91. Studies of the caudate and frontal neuronal activity of animals in identical behavioral tasks reveal cells which demonstrate significant task-related responses, but do not respond to the same stimuli or movements when they occur independently of the task [107]. However, beyond this general tendency, the detailed comparisons of the neuronal responses in the anterior caudate and frontal regions in identical tasks have led to different results. Some studies have 13, 59, 118and some have not [86], found cellular responses in the caudate nucleus with similar functional roles to frontal regions. In some studies the main difference between the anterior caudate and frontal regions appeared to be in the proportion of task-related neurons to all recorded cells 107, 113.

The caudate nucleus largely receives anatomical input from frontal and temporo-parietal cortical areas 63, 64, 72, 85, 102and sends output fibers to globus pallidus and other regions of the basal ganglia, forming anatomical loops with these structures [6]. Anatomically, the caudate consists of separate histochemically distinct compartments which appear somewhat similar to cortical columns [56]. The cortical areas project to the caudate nucleus in a highly organized way; different cortical regions project principally to different compartments of the caudate nucleus [102]. Part of the fronto-caudate loop returns back to Brodmann area 46 in prefrontal cortex [83]. Another part projects to Brodmann area 6 of the premotor cortex [60].

Pathology of caudate nucleus in human patients after hemorrhagic stroke produces cognitive changes among other symptoms 21, 22, 29, 80, 120, 124. Schizophreniform psychoses have been associated with a familial (or idiopathic) basal ganglia calcification [51]. Dementia in patients with Huntington disease has been correlated with the caudate glucose hypometabolism [71]. It was also found that schizophrenic patients have higher D₂ dopamine receptor densities in the caudate nucleus as compared to normal subjects [125]. Magnetic resonance imaging (MRI) abnormalities of the caudate nucleus have been reported in schizophrenia [23]and depression 70, 117. Neuroimaging studies of children with attention-deficit hyperactivity disorder reveal a reduced size with a reversed abnormal asymmetry [62]and hypoperfusion [76]of the caudate nuclei. These children are normal in rapid automatic covert shifts of attention controlled by posterior, parietal attention system. However, where the covert shifts of attention are slower and more likely to be controlled by the anterior, frontal attention system, children with attention-deficit hyperactivity disorder are significantly worse than their normal counterparts [121]. Abnormally high glucose metabolism and local blood flow are found in the caudate and anterior frontal regions in patients with obsessive-compulsive disorder 14, 15, 20, 105, which decrease toward a normal range in those patients who respond well to either a drug or behavioral therapy 15, 20. These findings suggest that the anterior attention deficit and obsessive-compulsive disorder may depend on fronto-caudate circuitry as well.

Lesions due to non-hemorrhagic stroke strictly localized to the caudate nucleus rarely cause neurological symptoms and their major deficits may be cognitive, including psychiatric symptoms and behavioral problems. The cognitive impairments often have acute onset and may include memory, language or attention disturbances, as well as abulia, disinhibition and deficits in planning, problem solving and personality [82]. These symptoms are similar to the effects produced by prefrontal lesions [77]. The severity of these changes has been shown to correlate with the size and localization of lesion within the caudate nucleus (e.g. dorsolateral versus ventromedial caudate) but not with the lateralization [82]. Bilateral lesions tend to cause more severe cognitive deficits than do unilateral lesions 82, 106.

Electrical stimulations [122]and depth recordings [17]of patients demonstrated the caudate’s relation to language and verbal memory. Lesions involving caudate nucleus may produce aphasia with semantic or phonemic paraphasia and disturbances of naming, oral reading, aural and reading comprehension of words, word associations, spelling, articulation and other aphasic symptoms with clustering different from classical cortical, thalamic or putaminal aphasic syndromes 25, 33, 34, 36.

Thus, the present brief review of anatomical input and output of the caudate nucleus and behavioral effects of its lesions suggests that the circuitry of multiple cortical areas may involve the caudate region. Most relevant to cognitive functions of the head of the caudate nucleus seem to be the dorsolateral prefrontal and the anterior cingulate loops which both involve the caudate nucleus 6, 45, 83.

It is possible to study the activity of neurons in various brain regions during cognitive tasks in certain patients who have depth electrodes for their diagnosis and therapy 16, 18, 61, 88, 89, 110. In our earlier work, we have described the neuronal activity in dorsolateral prefrontal cortex areas 46 and 10 [1]and in Broca’s area including Brodmann’s areas 44 and 9 [19]in visual word processing and object naming tasks. In the present study, we recorded neuronal activity directly from the head of the caudate nucleus in human patients in identical object naming and visual word processing tasks and compared the results to similar cortical studies. Part of these results has been reported recently in an abstract form 4, 5. The goal of the present study is to examine the role that the caudate nucleus plays in language tasks. We start out by showing clear evidence of increased neuronal activity in the caudate specific to visual words as compared to pseudowords. This early activation appeared to relate to semantics and is separate from a later activation related to word sound. Next we show that the early semantic activations occur in these same cells during object naming and that they do not depend upon making a specific response (motor output). The caudate semantic activation is not specific to words, but appears to occur to other stimuli for which a semantic analysis is possible (i.e. objects). Finally, in a section on memory, we show that the increase of neuronal activity to word stimuli does not occur during the task of memory retrieval where no semantic task is required. This suggests the selectivity of firing increase for semantic processing.