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Executive processes in Parkinson's disease--random number generation and response suppression.

In producing random numbers, subjects typically deviate systematically from statistical randomness. It is considered that these biases reflect constraints imposed by underlying structures and processes, rather than a deficient concept of randomness. Random number generation (RNG) places considerable demands on executive processes, and provides a possibly useful tool for their investigation. A group of patients with Parkinson's disease (PD) and a group of controls were tested on a RNG task, both alone and with a concurrent attention-demanding task (manual tracking). Both groups showed the biases in RNG described previously, including a strong counting tendency and repetition avoidance. Overall RNG performance did not differ between the groups, although differences were found in the counting biases in the patient and control groups, with the controls showing a bias towards counting in twos, and the patients a bias towards counting in ones. The secondary task reversed the bias shown by controls and exacerbated the bias in the patients. A network modulation model may help explain many of the features of RNG. We suggest that naturally biased output from an associative network must be actively suppressed by an attention-demanding, limited-capacity process. This suppression may be disrupted by the pathophysiology of PD and by concurrent tasks. Convergent evidence from various sources is discussed which supports a role of the dorsolateral prefrontal cortex (DLPFC) in this process.

Aged↗

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli: a 15O-PET study.

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.

Adult↗

The calculating brain: an fMRI study.

To explore brain areas involved in basic numerical computation, functional magnetic imaging (fMRI) scanning was performed on college students during performance of three tasks; simple arithmetic, numerical magnitude judgment, and a perceptual-motor control task. For the arithmetic relative to the other tasks, results for all eight subjects revealed bilateral activation in Brodmann's area 44, in dorsolateral prefrontal cortex (areas 9 and 10), in inferior and superior parietal areas, and in lingual and fusiform gyri. Activation was stronger on the left for all subjects, but only at Brodmann's area 44 and the parietal cortices. No activation was observed in the arithmetic task in several other areas previously implicated for arithmetic, including the angular and supramarginal gyri and the basal ganglia. In fact, angular and supramarginal gyri were significantly deactivated by the verification task relative to both the magnitude judgment and control tasks for every subject. Areas activated by the magnitude task relative to the control were more variable, but in five subjects included bilateral inferior parietal cortex. These results confirm some existing hypotheses regarding the neural basis of numerical processes, invite revision of others, and suggest productive lines for future investigation.

Adult↗

The cognitive and neuroanatomical correlates of multitasking.

Patients who show the "strategy application disorder" can show deficits restricted to situations requiring multitasking, but the precise neuroanatomical and cognitive correlates of this problem have been rarely investigated. In this study, 60 people with circumscribed cerebral lesions and 60 age- and IQ-matched controls were given a multitasking procedure which allowed consideration of the relative contributions of task learning and remembering, planning, plan-following and remembering one's actions to multitasking performance. Lesions to the left posterior cingulate and forceps major regions gave deficits on all measures except planning. Remembering task contingencies after a delay was also affected by lesions in the region of the left anterior cingulate, and rule-breaking and failures of task switching were additionally found in people with lesions affecting the medial and more polar aspects of Brodmann's areas 8, 9 and especially 10. Planning deficits were associated with lesions to the right dorsolateral prefrontal cortex (RDLPFC). A theory of the relationships between the cognitive constructs underpinning multitasking was tested using structural equation modelling. The results suggest that there are three primary constructs that support multitasking: retrospective memory, prospective memory, and planning, with the second two drawing upon the products of the first. It is tentatively suggested that the left anterior and posterior cingulates together play some part in the retrospective memory demands, while the prospective memory and planning components make demands on processes supported by the left areas 8, 9 and 10 and the RDLPFC respectively.

Adolescent↗

Cortical control of ocular saccades in humans: a model for motricity.

Our knowledge of the cortical control of saccadic eye movements (saccades) in humans has recently progressed mainly thanks to lesion and transcranial magnetic stimulation (TMS) studies, but also to functional imaging. It is now well-known that the frontal eye field is involved in the triggering of intentional saccades, the parietal eye field in that of reflexive saccades, the supplementary eye field (SEF) in the initiation of motor programs comprising saccades, the pre-SEF in learning of these programs, and the dorsolateral prefrontal cortex (DLPFC) in saccade inhibition, prediction and spatial working memory. Saccades may also be used as a convenient model of motricity to study general cognitive processes preparing movements, such as attention, spatial memory and motivation. Visuo-spatial attention appears to be controlled by a bilateral parieto-frontal network comprising different parts of the posterior parietal cortex and the frontal areas involved in saccade control, suggesting that visual attentional shifts and saccades are closely linked. Recently, our understanding of the cortical control of spatial memory has noticeably progressed by using the simple visuo-oculomotor model represented by the memory-guided saccade paradigm, in which a single saccade is made to the remembered position of a unique visual item presented a while before. TMS studies have determined that, after a brief stage of spatial integration in the posterior parietal cortex (inferior to 300 ms), short-term spatial memory (i.e. up to 15-20 s) is controlled by the DLPFC. Behavioral and lesion studies have shown that medium-term spatial memory (between 15-20 s and a few minutes) is specifically controlled by the parahippocampal cortex, before long-term memorization (i.e. after a few minutes) in the hippocampal formation. Lastly, it has been shown that the posterior part of the anterior cingulate cortex, called the cingulate eye field, is involved in motivation and the preparation of all intentional saccades, but not in reflexive saccades. These different but complementary study methods used in humans have thus contributed to a better understanding of both eye movement physiology and general cognitive processes preparing motricity as whole.

Cerebral Cortex↗

Spatially directed movement and neuronal activity in freely moving monkey.

The abilities to plan a series of movements and to navigate within the environment require the functions of the frontal and ventromedial temporal lobes, respectively. Neuropsychological studies posit the existence of egocentric (prefrontal) and allocentric (ventromedial temporal) spatial frames of reference that mediate these functions. To examine neural mechanisms underlying egocentric and allocentric guidance of movement, we have developed behavioral and neurophysiological techniques for freely moving monkey. In this chapter, we provide evidence that the dorsolateral prefrontal cortex is important for egocentric spatial tasks in both the visual and tactile modalities, but it does not contribute to performance of an allocentric spatial task. Moreover, neurophysiological recordings indicate that prefrontal neurons are involved in monitoring the spatial nature of behavioral sequences in an egocentric memory task. In contrast, hippocampal neurons are active during spatially directed locomotion, apparently reflecting the monkey's location in a testing room. This discharge is independent of the task's contingencies.

Animals↗

The mental self.

In meditation both the quality and the contents of consciousness may be voluntarily changed, making it an obvious target in the quest for the neural correlate of consciousness. Here we present the results of a positron emission tomography study of yoga nidra relaxation meditation when compared with the normal resting conscious state. Meditation is accompanied by a relatively increased perfusion in the sensory imagery system: hippocampus and sensory and higher order association regions, with decreased perfusion in the executive system: dorsolateral prefrontal cortex, anterior cingulate gyrus, striatum, thalamus, pons, and cerebellum. To identify regions active in both systems we performed a principal component analysis of the results. This separated the blood flow data into two groups of regions, explaining 25 and 18% of their variance: One group corresponded to the executive system, and the other to the systems supporting sensory imagery. A small group of regions contributed considerably to both networks: medial parietal and medial prefrontal cortices, together with the striatum. The inclusion of the striatum and our subsequent finding of increased striatal dopamine binding to D2 receptors during meditation suggested dopaminergic regulation of this circuit. We then investigated the neural networks supporting episodic retrieval of judgments of individuals with different degrees of self-relevance, in the decreasing order: self, best friend, and the Danish queen. We found that all conditions activated a medial prefrontal - precuneus/posterior cingulate cortex, thalamus, and cerebellum. This activation occurred together with the activation of the left lateral prefrontal/temporal cortex. The latter was dependent on the requirement of retrieval of semantic information, being most pronounced in the "queen" condition. Transcranial magnetic stimulation, targeting precuneus, was then applied to the medial parietal region to transiently disrupt the normal function of the circuitry. We found a decreased efficiency of retrieval of self-judgment compared to the judgment of best friend. This shows that the integrity of the function of precuneus is essential for self-reference, but not for reference to others.

Brain↗

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory.

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the 'maintenance'-function of WM and the 'manipulation and monitoring'-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

Age Factors↗

GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia.

The pathophysiology of schizophrenia involves dysfunction of the dorsolateral prefrontal cortex, and this dysfunction may be related to alterations in GABA neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia requires knowledge of which subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons are of interest in this regard because their axon terminals form distinctive vertical arrays (termed 'cartridges') which synapse exclusively with the axon initial segments of pyramidal neurons, the principal class of cortical excitatory neurons. We evaluated the integrity of chandelier neuron cell bodies and axon cartridges in PFC areas 9 and 46 of schizophrenic subjects using immunocytochemical techniques and antibodies against parvalbumin and the GABA membrane transporter GAT-1. Schizophrenic subjects did not differ from matched control subjects in the relative density, laminar distribution or size of parvalbumin-containing neurons. In contrast, the density of GAT-1-immunoreactive chandelier neuron axon cartridges was decreased by 40% in schizophrenic subjects compared to both normal controls and subjects with other psychiatric disorders. The axon terminals of other subclasses of GABA neurons did not appear to be similarly affected. These findings suggest that disturbed GABA neurotransmission in the PFC of schizophrenic subjects may be due to a selective alteration of GAT-1 protein in the axon terminals of chandelier neurons.

Humans↗

A microelectrode drive for long term recording of neurons in freely moving and chaired monkeys.

An electrode drive is described for recordings of neurons in freely moving and chaired monkeys during the performance of behavioural tasks. The electrode drives are implanted for periods of up to 6 months, and can advance up to 42 electrodes using 14 independent drive mechanisms. The drive samples 288 points within a 12 mmx12 mm region, with 15 mm of electrode travel. Major advantages are that recordings are made in freely moving monkeys, and these recordings can be compared with those in chaired experiments; waveforms of single neurons are stable, enabling prolonged recordings of the same neurons across periods of days; recordings can be made throughout the brain, including the dorsolateral prefrontal cortex and hippocampus; the drive accommodates both sharp microelectrodes and fine wire assemblies such as tetrodes.

Action Potentials↗

The impact of repetitive transcranial magnetic stimulation on pituitary hormone levels and cortisol in healthy subjects.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a new therapeutic tool in the treatment of affective disorders but only few studies on its safety exist. We aimed to determine the impact of rTMS on (neuro)endocrinological serum levels by a placebo-controlled cross-over study. METHODS: 23 healthy subjects were stimulated by rTMS in a typical paradigm used in the treatment of depression (coil placed over left dorsolateral prefrontal cortex, 10 and 20 Hz stimulation). Placebo, infrathreshold, and suprathreshold stimulation were applied in random order. The serum levels of cortisol, prolactin, FSH, and TSH were measured before and after stimulation. RESULTS: After infrathreshold stimulation, cortisol and TSH serum levels decreased mildly but significantly. All other stimulations had no significant impact on hormone levels. In female, but not in male, subjects placebo stimulation yielded a significant increase of prolactin. CONCLUSIONS: rTMS as applied for the treatment of depression leads to only very mild and safe changes of hormones. These changes, in particular the decrease of cortisol levels, might explain in part the efficacy of rTMS.

Adult↗

Perseveration in schizophrenia: failure to generate a plan and relationship with the psychomotor poverty subsyndrome.

Although perseveration in the Wisconsin Card Sorting Test (WCST) has been studied extensively in schizophrenia, the underlying cognitive dysfunctions are not yet clear. In schizophrenia, perseveration has been found to relate to frontal and striatal abnormalities. Therefore, both a failure to generate a plan as seen in patients with frontal abnormalities, or a failure to execute a plan as observed in Parkinson patients, who suffer primarily from striatal abnormalities, could explain perseveration in schizophrenia. The aim of the present study was to distinguish between these two cognitive dysfunctions, which are described by Frith in his routes-to-action model. The main difference between these dysfunctions is the ability to use external guidance. In the present study, 39 schizophrenic patients and 36 healthy controls were assessed with the California Verbal Learning Test (CVLT) and the WCST, in which use of external guidance can be measured, and with the Positive and Negative Syndrome Scale (PANSS) to determine the relationship with symptomatology. The results showed that half of the schizophrenic patients showed perseveration, which could be explained by a failure to generate a plan and was related to the psychomotor poverty subsyndrome. No evidence was found for a failure to execute a plan. Type of antipsychotic medication used (atypical vs. typical) proved not relevant. The results are discussed in the light of evidence for involvement of the dorsolateral prefrontal cortex in perseveration in schizophrenia.

Adult↗

Gender differences in the effect of repetitive transcranial magnetic stimulation in schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) can be beneficial in schizophrenia, possibly through a reversal of pre-treatment hypofrontality. Twelve schizophrenic patients (8 men, 4 women) were treated with high-frequency rTMS of the dominant dorsolateral prefrontal cortex. Their performance of the number-connection test, which assesses cognitive processes related to the frontal lobe, was evaluated before and after rTMS. Women improved markedly on the test after rTMS, whereas men did not show a significant change. There were no corresponding sex differences in clinical measures after rTMS. The preliminary findings of sex differences in the response to rTMS, as reflected by performance on the number-connection test, suggest the need for investigations of a greater number of schizophrenic men and women with a more intensive examination of the effects of rTMS on cognitive functions.

Adult↗

Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS.

In previous studies, fast repetitive transcranial magnetic stimulation (rTMS) with a frequency > 1 Hz demonstrated substantial antidepressant effects compared to sham rTMS. However, it is not clear whether fast rTMS is superior to slow rTMS (frequency < or = 1 Hz) which is safe at therapeutically promising higher intensities. The aim of this double-blind study was to compare the action of fast, slow and sham rTMS. Eighteen patients with pharmacotherapy-resistant major depression were randomized to receive fast (10 Hz), slow (0.3 Hz) or sham rTMS with 250 stimuli/day for 5 successive days. rTMS was applied at 90% motor threshold intensity to the left dorsolateral prefrontal cortex. Scores on the Hamilton Depression Rating Scale (HDRS), but not on the Montgomery-Asberg Depression Rating Scale (MADRS), showed a statistically significant time x group interaction with a reduction of 19% after slow rTMS. However, the effect was clinically marginal and not reflected by self-rating scores. Verbal memory and reaction performance were not impaired after rTMS, and there was even a statistically significant time x group interaction with improvement of verbal memory performance after fast rTMS. In conclusion, this study further supported the safety of rTMS but does not show any clinically meaningful antidepressant efficacy of rTMS at 250 daily stimuli over 5 days in pharmacotherapy-refractory major depression.

Adult↗

2-Deoxyglucose uptake during vocalization in the squirrel monkey brain.

In the squirrel monkey (Saimiri sciureus), the cerebral 2-deoxyglucose uptake was compared between animals made to vocalize by electrical stimulation of the periaqueductal grey and animals stimulated in the same structure, but sub-threshold for vocalization. A significantly higher 2-deoxyglucose uptake in the vocalizers than the non-vocalizers was found in the dorsolateral prefrontal cortex, supplementary and pre-supplementary motor area, anterior and posterior cingulate cortex, primary motor cortex, claustrum, centrum medianum, perifornical hypothalamus, periaqueductal grey, intercollicular region, dorsal mesencephalic reticular formation, peripeduncular nucleus, substantia nigra, nucl. ruber, paralemniscal area, trigeminal motor, principal and spinal nuclei, solitary tract nucleus, nucl. ambiguus, nucl. retroambiguus, nucl. hypoglossus, ventral raphe and large parts of the medullary reticular formation. The study makes clear that vocalization, even in the case of genetically pre-programmed patterns, depends upon an extensive network, beyond the well-known periaqueductal grey, nucl. retroambiguus and cranial motor nuclei pathway.

Animals↗

The effects of antipsychotic medication on saccadic eye movement abnormalities in Huntington's disease.

1. The study was a prospective open trial done to determine the effect of antipsychotic medication on saccadic eye movements in patients with Huntington's disease (HD). The authors tested 16 outpatients with HD, 8 of whom were drug free and 8 of whom were on antipsychotic medication. We also tested 24 healthy control subjects. 2. The antisaccade task was used to investigate the voluntary control of saccadic eye movements. Antisaccade latencies and error rates were used as outcome measures. Both HD patient groups showed significantly more antisaccade abnormalities than controls and the rate of abnormalities was very similar between the drug-free and medicated patient groups. 3. The results suggest that these abnormalities are related to underlying neuropathology rather than effects of medication. Either specific dysfunction of the dorsolateral prefrontal cortex or of the subcortical circuit connecting this cortical area to the superior colliculus via the striatum are likely to be responsible for the generation of such antisaccade eye movement abnormalities.

Adult↗

Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation.

We studied the effect of repetitive transcranial magnetic stimulation (rTMS) on changes in regional cerebral blood flow (rCBF) as revealed by positron emission tomography (PET) while subjects performed a 2-back verbal working memory (WM) task. rTMS to the right or left dorsolateral prefrontal cortex (DLPFC), but not to the midline frontal cortex, significantly worsened performance in the WM task while inducing significant reductions in rCBF at the stimulation site and in distant brain regions. These results for the first time demonstrate the ability of rTMS to produce temporary functional lesions in elements of a neuronal network thus changing its distributed activations and resulting in behavioral consequences.

Adult↗

Parallel distributed processing neuroimaging in the Stroop task using spatially filtered magnetoencephalography analysis.

Parallel distributed processing neuroimaging in the Stroop color word interference task in five healthy subjects was studied. The total reaction time was set at 650 ms with a time window of 200 ms in steps of 50 ms. Spatially filtered magnetoencephalography analysis, as used in synthetic aperture magnetometry, was used. Neural activation began in the left posterior parietal-occipital area (150-250 ms post-stimulus), followed by the right prefrontal polar area (250-350 ms), the left dorsolateral prefrontal cortex (250-400 ms), and the mid- to lower- primary motor area (350-400 ms). Successive and temporally overlapping activation of various cortical regions were successfully estimated within a short 200 ms time interval, contrary to previous positron emission tomography and fMRI studies.

Adult↗