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Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study.

Several studies with functional and structural brain-imaging techniques support the hypothesis that responders and non-responders to clozapine could show a different pattern of cerebral dysfunction. Thirty-nine neuroleptic-refractory schizophrenic patients were studied with 99Tc-labelled hexamethyl-propylene-aminoxime (HMPAO) and SPECT, while on classical neuroleptics and after 6 months of treatment with clozapine. The perfusion differences between responders and non-responders to clozapine were studied in the regions included within the dorsolateral and orbitofrontal fronto-striato-thalamic circuits, as well as the predictive value of these parameters. These values were compared to those of a normal database, and between both treatments within the two groups. On-neuroleptic perfusion in non-responders was lower in the thalamus, basal ganglia and dorsolateral prefrontal cortex. Thalamus and right prefrontal perfusion regions were selected as response predictors by a discriminant analysis. Thalamic and left basal ganglia activities while on neuroleptics were lower only in non-responders with respect to the normal subjects. Perfusion changes were only observed in the responder group in thalamus and basal ganglia. Study of regional perfusion may contribute to the prediction of clozapine response.

Adult↗

Visuospatial imagery is a fruitful strategy for the digit span backward task: a study with near-infrared optical tomography.

Our newly developed 64-channel time-resolved optical tomographic imaging system using near-infrared light enables us to obtain a quantitative image of hemoglobin concentration changes associated with neuronal activation in the human brain ¿H. Eda, I. Oda, Y. Ito, Y. Wada, Y. Oikawa, Y. Tsunazawa, M. Takada, Y. Tsuchiya, Y. Yamashita, M. Oda, A. Sassaroll, Y. Yamada, M. Tamura, Multi-channel time-resolved optical tomographic imaging system, Rev. Sci. Instrum., 70 (1999) 3595-3602. Here, we used this optical imaging system to demonstrate that the backward digit span (DB) task activated the dorsolateral prefrontal cortex (DLPFC) of each hemisphere more than the forward digit span (DF) task in healthy adult volunteers, and higher performance of the DB task was closely related to the activation of the right DLPFC. These results suggest that visuospatial imagery is a useful strategy for the DB task. Optical tomography described here is a new modality of neuropsychological studies.

Adult↗

Neural activities during Wisconsin Card Sorting Test--MEG observation.

The present study recorded activities of magnetoencephalography (MEG) to the presentation of cards, and to the presentation of feedback signals in 12 normal subjects while they performed the Wisconsin Card Sorting Test (WCST), to observe temporal and spatial processing during the task. The MEG responses were compared between two different conditions in the presentation both of cards and of feedback signals: the cards proceeded by the first wrong [W1st(C)] and by the 4th correct feedback signals [C4th(C)]; and the feedback of the first wrong [W1st(FB)] and the 4th correct signals [C4th(FB)]. A multi-dipole model, brain electric source analysis (BESA), was used to explore the dipole sources responsible for the MEG activities. We found that MEG activity differences between the W1st(C) and the C4th(C) condition occurred in the period of 190-220 ms (M190 and M200), and 300-440 ms (M300 and M370) mainly at the supramarginal gyrus, the dorsolateral prefrontal, and the middle and inferior frontal gyrus. MEG differences between the W1st(FB) and the C4th(FB) condition occurred 460-640 ms (M460) after the presentation of the feedback signals, with the activation of the dorsolateral prefrontal cortex and the middle frontal cortex. No significant location differences were found between the frontal responses (M370) of the W1st(C) and M460 of the W1st(FB). Our results proved that the WCST task activates a broad frontal area and the parieto-frontal network across time streaming. Both shifting attention to the wrong feedback and enhanced visual working memory to the sorting shifting condition of the card presentation occur in the same areas at different time points.

Adult↗

Consistency of inter-trial activation using single-trial fMRI: assessment of regional differences.

Recently, the technique of single-trial fMRI was introduced, which allows the assessment of hemodynamic responses to single task executions (e.g. sensory, motor, or cognitive). In this study, single-trial fMRI was used to examine regional differences in the inter-trial consistency (ITC) of brain activity related to the processing of a dynamic visuo-spatial imagery task. For every single trial, a t-statistic assessing task-related activation was calculated and thresholded at a p-value of P < or =l0.05 (uncorrected). The percentage of trials with t-values above the threshold was used to assess differences in the consistency of brain activity in occipital, parietal, premotor and prefrontal regions of interest. While most of these regions showed activation which was highly consistent across trials, the consistency of activation was significantly reduced in the dorsolateral prefrontal cortex. We hypothesize that the consistency of activation across trials may be interpreted as an indicator of the functional relevance of a brain region for processing and solving a cognitive task. Thus, the analysis concept presented here has the potential to provide new insights into the neuro-cognitive mechanisms of human information processing. In addition, the results of this study confirm that averaging across trials might result in a significant loss of information about functional neuroanatomy. Regions which are active in some trials only, which show only weak activity increases, or whose activity is not constant and time-locked, might not show up in averaged activation maps and could thus erroneously be interpreted as irrelevant for task processing.

Adult↗

A computational approach to control in complex cognition.

Cognitive deficits associated with dorsolateral prefrontal cortex (DLPFC) damage are often most apparent in higher cognitive tasks that involve problem solving and managing multiple goals. However, computational models of prefrontal deficits on such tasks are difficult to construct. Problem solving is most naturally modeled with symbolic systems (e.g. production systems), but the effects of lesions are most naturally modeled with subsymbolic systems (neural networks). We show that when we adopt a simple and plausible model of neural computation, there is a natural and explicit mapping from symbolic, goal-driven cognition onto neural computation. We exploit this mapping to construct a neural network model that is capable of solving complex problems in the Tower of London task. The model leads to a specific hypothesis about the role of DLPFC in such tasks, namely, that DLPFC represents internally generated subgoals that modulate competition among posterior representations. When intact, the model accurately simulates the behavior of college students even on the most difficult problems. Furthermore, when the subgoal component is lesioned, it accurately simulates the behavior of prefrontal patients, including the fact that their deficits are most apparent on the most difficult tasks and that they have special difficulty with tasks that require inhibiting a prepotent response.

Cognition↗

Temporal isolation of the neural correlates of spatial mnemonic processing with fMRI.

The use of cognitive subtraction to study the neural substrates of the maintenance component of spatial working memory in humans relies upon the assumptions of the pure insertion of cognitive processes and a linear transform of neural activity to neuroimaging signal. Here, functional changes attributable to the memory requiring phase (referred to as the retention delay) of a spatial working memory task were temporally discriminated from those attributable to other behavioral subcomponents within trials using an experimental design that is argued to obviate these assumptions, as well as permit a joint test of their validity. The hypothesis that the assumptions of cognitive subtraction (as applied to neuroimaging) hold in general was not supported. Functional changes attributable to the retention delay were detected in the dorsolateral prefrontal cortex as well as in other cortical regions in a subset of the subjects, and in the right frontal eye field and right superior parietal lobule of all subjects (n=5). These results support models in which these regions are involved in maintaining spatial representations in humans. In addition, nearly all regions that evidenced such functional changes during the retention delay also evidenced functional changes during behaviors that did not require spatial working memory. This result tends to dispute models which posit the existence of gross neuroanatomical regions involved in solely mnemonic function.

Adult↗

Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson's disease.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide the means to studying in vivo the neurochemical, hemodynamic or metabolic consequences of the degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD). The extent of striatal dopaminergic denervation can be quantified with radiotracers as [18F]FDopa for PET and [123I]tropanes for SPECT. There are other radiotracers such as [11C]Dopa and meta-tyrosines as well as PET tracers for uptake sites. Striatal uptake of [18F]FDopa and [123I]tropanes is markedly decreased in PD, more in the putamen than in the caudate nucleus, and inversely correlates with the severity of motor signs and with duration of disease. PET and SPECT make possible the assessment by noninvasive means of the changes in dopamine receptor density, the effect of neuronal transplants or neuroprotective treatments in PD patients, or the nigrostriatal dopaminergic function in at-risk subjects. Activation studies using cerebral blood flow and metabolism measurements during a motor task reveal an impaired ability to activate the supplementary motor area and dorsolateral prefrontal cortex in PD. This functional disability is reversed by the use of dopaminergic medication or by surgical treatment by pallidotomy or deep brain stimulation. The differential diagnosis between PD and multiple system atrophy, progressive supranuclear palsy or corticobasal degeneration is not yet clearly established by PET and SPECT, even though these syndromes have some particular neurochemical and metabolic profiles. On the other hand, PET and SPECT are useful for distinguishing PD from Dopa-responsive dystonia, or for assessing the integrity of the nigrostriatal dopaminergic pathway in atypical cases of postural tremor or iatrogenic parkinsonian syndromes.

Aging↗

The role of frontal and temporal lobes in visual discrimination task--depth ERP studies.

Visual event-related potentials were simultaneously recorded from different anatomical structures within frontal and temporal lobes in 12 epileptic patients. A simple discrimination task was performed to complement previous studies on the localization of P3 generators in the human brain. The role of multiple cortical structures in the generation of both P3a and P3b components was confirmed. Activities contemporary to a visual P3b were recorded in the hippocampus, amygdala and temporal pole. Anterior cingulate and orbitofrontal cortices-generated activities more closely related in time to the surface P3a. Earlier events related to visual discrimination took place in more lateral sites of the frontal lobe, but their contribution to the scalp P3 remains uncertain. Subsequently, mutual temporal relations among single generators were analyzed. The results suggested a processing-level hierarchy within the neural network for directed attention with a key role played by the dorsolateral prefrontal cortex.

Adult↗

Continuity between waking activities and dream activities.

Empirical studies largely support the continuity hypothesis of dreaming. Despite of previous research efforts, the exact formulation of the continuity hypothesis remains vague. The present paper focuses on two aspects: (1) the differential incorporation rate of different waking-life activities and (2) the magnitude of which interindividual differences in waking-life activities are reflected in corresponding differences in dream content. Using a correlational design, a positive, non-zero correlation coefficient will support the continuity hypothesis. Although many researchers stress the importance of emotional involvement on the incorporation rate of waking-life experiences into dreams, formulated the hypothesis that highly focused cognitive processes such as reading, writing, etc. are rarely found in dreams due to the cholinergic activation of the brain during dreaming. The present findings based on dream diaries and the exact measurement of waking activities replicated two recent questionnaire studies. These findings indicate that it will be necessary to specify the continuity hypothesis more fully and include factors (e.g., type of waking-life experience, emotional involvement) which modulate the incorporation rate of waking-life experiences into dreams. Whether the cholinergic state of the brain during REM sleep or other alterations of brain physiology (e.g., down-regulation of the dorsolateral prefrontal cortex) are the underlying factors of the rare occurrence of highly focused cognitive processes in dreaming remains an open question. Although continuity between waking life and dreaming has been demonstrated, i.e., interindividual differences in the amount of time spent with specific waking-life activities are reflected in dream content, methodological issues (averaging over a two-week period, small number of dreams) have limited the capacity for detecting substantial relationships in all areas. Nevertheless, it might be concluded that the continuity hypothesis in its present general form is not valid and should be elaborated and tested in a more specific way.

Adult↗

Frontostriatal system in planning complexity: a parametric functional magnetic resonance version of Tower of London task.

In the present study, we sought to investigate which brain structures are recruited in planning tasks of increasing complexity. For this purpose, a parametric self-paced pseudo-randomized event-related functional MRI version of the Tower of London task was designed. We tested 22 healthy subjects, enabling assessment of imaging results at a second (random effects) level of analysis. Compared with baseline, planning activity was correlated with increased blood oxygenation level-dependent (BOLD) signal in the dorsolateral prefrontal cortex, striatum, premotor cortex, supplementary motor area, and visuospatial system (precuneus and inferior parietal cortex). Task load was associated with increased activity in these same regions. In addition, increasing task complexity was correlated with activity in the left anterior prefrontal cortex, a region supposed to be specifically involved in third-order higher cognitive functioning.

Adult↗

Practice-related effects demonstrate complementary roles of anterior cingulate and prefrontal cortices in attentional control.

The purpose of this study was to test the hypothesis that the dorsolateral prefrontal cortex (DLFPC), not the anterior cingulate cortex (ACC), plays the predominant role in implementing top-down attentional control. To do so, we used fMRI to examine practice-related changes in neural activity during a variant of the Stroop task. The results indicated that the DLPFC's activity decreased gradually as the need for control was reduced (as indexed by behavioral measures), while the ACC's activity dropped off rapidly. Such a pattern is consistent with the DLPFC taking a leading role in implementing top-down attentional control and the ACC being involved in other aspects of attentional control, such as response-related processes. In addition, with practice, there was a reduction in activity within cortical systems handling the processing of task-irrelevant information capable of interfering with task performance. This finding suggests that with practice the brain is capable of identifying and strategically inhibiting such processing.

Adult↗

Context-dependent cortical activation in response to financial reward and penalty: an event-related fMRI study.

An event-related fMRI technique was used to assess neural responses to financial reward and penalty during a simple gambling task. We attempted to determine whether brain activities are dependent on the unique context of an event sequence. Thirty-six healthy volunteers participated in the study. The task was to guess the color of the suit of a card on each trial and to respond by pressing a button. Every correct response ("win") and incorrect response ("loss") was associated with financial reward and penalty, respectively. The magnitude of reward or penalty in each trial did not change; however, the subjects' self-reported emotional arousal was significantly higher for the events of "the fourth win of four wins in a row" and "the fourth loss of four losses in a row." We also found that the bilateral anterior cingulate and medial prefrontal cortices were specifically activated when the subjects experienced "the fourth win of four wins in a row" and "the fourth loss of four losses in a row." When the subjects experienced "a win following four losses in a row" or "a loss following four wins in a row," the right dorsolateral prefrontal cortex was specifically activated. Our data indicate that there exist brain activities associated with the event-sequence context in which abstract reward or penalty is received. These context-dependent activities appear to be crucial for adapting oneself to new circumstances and may account for clinical symptoms of various mental illnesses in which dysfunction of these regions has been reported.

Adolescent↗

rCBF changes elicited by rTMS over DLPFC in humans.

Recently, repetitive TMS (rTMS) has been used as a potential treatment for depression. Several studies have shown antidepressant effects of rapid rTMS over the left dorsolateral prefrontal cortex (DLPFC), whereas some studies suggested the effectiveness of slow rTMS over the right DLPFC. Despite the growing interest in therapeutic application of rTMS, the precise mechanisms for rTMS over the DLPFC are still unknown. To clarify these mechanisms for slow rTMS over the right prefrontal cortex, we measured regional cerebral blood flow (rCBF) during real or sham rTMS and after stimulation using repeated l5O-labeled H2O PET scanning in seven healthy subjects. We found that slow rTMS over the right DLPFC could produce significant rCBF increase in the ipsilateral anterior cingulate cortex (ACC) during stimulation as compared with sham stimulation. The lasting activation occurred in the ipsilateral medial prefrontal cortex, contralateral ventrolateral PFC, and the contralateral ventral striatum. These data indicate that slow rTMS is able to produce rCBF changes in the paralimbic system and frontal cortex. We conclude that the lasting effect on the ventral striatum should reflect modulatory effects of rTMS over the DLPFC on the meso-limbic dopaminergic system that must play critical roles in antidepressant effects.

Brain Mapping↗

Repetitive transcranial magnetic stimulation for treating medication-resistant depression in Taiwan: a preliminary study.

BACKGROUND: We conducted an open trial to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in medication-resistant depression. This is the first study in Taiwan of rTMS for the treatment of depression. METHODS: A 2-week regimen of rTMS (100% of motor threshold, 5 Hz, 8 sec, 40 trains/20 min/day, 10 weekdays) applied to the left dorsolateral prefrontal cortex was administered to 11 patients with medication-resistant depression. RESULTS: Ten subjects completed 2 weeks' treatment with rTMS. Scores on the 21-item Hamilton Depression Rating Scale (HAM-D21) and Beck Depression Inventory decreased by 48% and 28%, respectively. Five patients were clinical responders (> or = 50% reduction in HAM-D21 score): 2 of these were in complete remission (HAM-D21 score < or = 7). Five patients were less responsive: 2 of these were partial responders (20-49% reduction in HAM-D21 score), whereas 3 did not improve. Younger versus older age was identified as a potential predictor of response to rTMS used as add-on therapy. CONCLUSION: Our preliminary results indicate that rTMS can improve mood in patients with medication-resistant depression, and can also potentially replace electroconvulsive therapy for certain types of medication-resistant depression. Future double-blind, placebo-controlled trials of rTMS are warranted.

Adult↗

Abnormal saccadic distractibility in patients with schizophrenia: a 99mTc-HMPAO SPET study.

Recent research has shown that some patients with schizophrenia have a severe impairment in the suppression of reflexive saccadic eye movements in the ANTI-saccade task. This saccadic distractibility has previously been found in patients with lesions of dorsolateral prefrontal cortex, implicating an abnormality of prefrontal cortex. The objective of the present study was to determine the contribution of these and other areas to the ANTI-saccadic abnormality in schizophrenia by functional neuroimaging. Using 99mtechnetium-HMPAO high resolution multidetector single-photon emission tomography, regional cerebral blood flow (rCBF) during performance of the ANTI-saccade eye-movement task was compared, by statistical parametric mapping, in ten male schizophrenic patients on stable antipsychotic medication who had a high distractibility error rate on the task, and eight similar patients who had normal distractibility error rates. Compared with the normal error group, the patients with high error rates showed significantly decreased rCBF bilaterally, in the anterior cingulate, insula, and in left striatum. These same patients also had increased perseverative errors on the Wisconsin Card Sort Test.

Adult↗

Changes in regional cerebral blood flow on recovery from depression.

We have previously described focal abnormalities of regional cerebral blood flow (rCBF) in the left dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex and angular gyrus in 40 patients with major depression. We now report on the patterns of change in rCBF in a subgroup of 25 of the same patients who were rescanned following clinical remission of depression. Fifteen patients were scanned when optimally matched for drug treatment (4) or drug free on both occasions (11). The other 10 patients were fully recovered but could not be matched for drug status for clinical and ethical reasons. In a paired comparison of the same patients when ill and following recovery it was evident that remission was associated with a significant increase in rCBF in the left DLPFC and medial prefrontal cortex including anterior cingulate. Increases in rCBF in the angular gyrus were not seen when the comparison of depressed and recovered scans was matched for medication. The previously described relationship between clinical symptoms and brain perfusion in the depressed state was no longer present in the recovered state; this supports the hypothesis of state relatedness. Thus, recovery from depression is associated with increases in rCBF in the same areas in which focal decreases in rCBF are described in the depressed state in comparison with normal controls.

Adult↗

The anatomy of melancholia--focal abnormalities of cerebral blood flow in major depression.

Using positron emission tomography (PET) and 15Oxygen, regional cerebral blood flow (rCBF) was measured in 33 patients with primary depression, 10 of whom had an associated severe cognitive impairment, and 23 age-matched controls. PET scans from these groups were analysed on a pixel-by-pixel basis and significant differences between the groups were identified on Statistical Parametric Maps (SPMs). In the depressed group as a whole rCBF was decreased in the left anterior cingulate and the left dorsolateral prefrontal cortex (P less than 0.05 Bonferroni-corrected for multiple comparisons). Comparing patients with and without depression-related cognitive impairment, in the impaired group there were significant decreases in rCBF in the left medial frontal gyrus and increased rCBF in the cerebellar vermis (P less than 0.05 Bonferroni-corrected). Therefore an anatomical dissociation has been described between the rCBF profiles associated with depressed mood and depression-related cognitive impairment. The pre-frontal and limbic areas identified in this study constitute a distributed anatomical network that may be functionally abnormal in major depressive disorder.

Adult↗

Relationship of behavioural and symptomatic syndromes in schizophrenia to spatial working memory and attentional set-shifting ability.

BACKGROUND: Behavioural syndromes (thought disturbance, social withdrawal, depressed behaviour and antisocial behaviour) offer a different perspective from that of symptomatic syndromes on the disability that may be associated with schizophrenia. Few studies have assessed their relationship with neuropsychological deficits. We hypothesized that these syndromes may represent behavioural manifestations of frontal-subcortical impairments, previously described in schizophrenia. METHOD: Long-stay inpatients (n=54) and community patients (n=43) with enduring schizophrenia were assessed, using measures of symptoms and behaviour and tests of executive functioning. The relationship between syndromes and neuropsychological function was assessed using multiple regression and logistic regression analyses. RESULTS: Significant associations were found between performance on the spatial working memory task and the psychomotor poverty symptomatic syndrome, and between attentional set-shifting ability and both disorganization symptoms and the thought disturbance behavioural syndrome. These results were not explained by the effect of premorbid IQ, geographical location, length of illness or antipsychotic medication. Length of illness was an independent predictor of attentional set-shifting ability but not of working memory performance. CONCLUSION: The specific relationship between negative symptoms and spatial working memory is consistent with involvement of the dorsolateral prefrontal cortex. The associations between difficulty with set-shifting ability and both disorganization symptoms and behaviours may reflect inability to generalize a rule that had been learned and impaired ability to respond flexibly. The specific relationship of illness duration to set-shifting ability may suggest progressive impairment on some executive tasks. The nature of these relationships and their neurobiological and rehabilitation implications are considered.

Adult↗