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Comparison of rhyming and word generation with FMRI.

Functional magnetic resonance imaging (FMRI) has been successfully used to non-invasively map language function, but has several disadvantages. These include severe motion sensitivity, which limits overt verbal responses in behavioral paradigms, such as word generation. The lack of overt responses prevents behavioral validation, making data interpretation difficult. Our objective was to compare the FMRI activation patterns of a novel silent rhyme determination task requiring a non-verbal response, to covert word generation from visually presented letters. Five strongly right-handed subjects performed both tasks during multi-slice coronal echo-planar T2*-weighted FMRI. Single subject activation maps were generated for each task by correlation analysis of single pixel time series to a boxcar reference function. These maps for the two tasks were separately interpolated to 256(3), transformed into Talairach space, summed, and thresholded at t>6. Combined activation maps from both tasks showed similar robust perisylvian language area activation, including inferior frontal gyrus, posterior superior temporal lobe, and fusiform gyrus. Subjects performed well on the rhyming task, which activated left hemisphere cortical regions more selectively than the word generation task. The rhyming task showed less activation than the word generation task in areas typically not considered specifically related to language function, such as the dorsolateral prefrontal cortex and anterior cingulate. The rhyming task is a useful tool for brain mapping and clinical applications, potentially more specific to cortical language areas than verbal fluency.

Adult↗

Disturbed functional brain interactions underlying deficient tactile object discrimination in Parkinson's disease.

Somatosensory discrimination of cuboid objects was studied in a group of healthy volunteers and patients with Parkinson's disease using regional cerebral blood flow (rCBF) measurements obtained with positron emission tomography (PET) and 15O labeled water [H2 15O]. A 6-[18F]-fluoro-L-dopa (FDOPA) PET scan demonstrated that the patients may be grouped into those with normal and those with abnormally lowA FDOPA uptake in the caudate nucleus. The categorical group comparisons revealed that task-induced rCBF increases were deficient in bilateral motor and sensory cortical areas in the Parkinson patients. Moreover, deficient rCBF increases were evident in the mesial and right dorsolateral prefrontal cortex for patients in a more advanced disease state, who showed low FDOPA uptake in the caudate nucleus. A principal component analysis (PCA), performed on the rCBF data, identified three patterns (principal components, PCs) that differentiated patients from normals. The first PC represented a right-hemisphere dominant, bilateral group of brain areas known to be involved in tactile exploration. A second PC reflected a cortical-subcortical pattern of functional interactions, comprising cortical areas important for working memory processes. The third group-differentiating PC revealed a pattern of functional interactions involving bilateral temporo-parieto-occipital association cortices, which was consistent with a hypothesized supramodal network necessary for object discrimination. In an additional subgroup analysis, greater expression of the third PC pattern predicted greater caudate FDOPA uptake in patients. Our neuroimaging data revealed a disturbance of distinct patterns of brain functional interactions related to the sensorimotor deficit in Parkinson's disease and to deficits of cognitive information processing deficits in the more advanced stage of Parkinson's disease.

Adult↗

The effects of surgical treatment of Parkinson's disease on brain function: PET findings.

Positron emission tomography allows a quantitative assessment of the impact of functional neurosurgery in Parkinson's disease (PD) by measuring regional cerebral flow and glucose and oxygen consumption as indicators of metabolic activity of specific brain regions. PET can also be used to study the dopaminergic nigrostriatal system, and therefore serves as a surrogate marker of the evolution of striatal grafts for PD. Pallidotomy has been associated with increased activation of premotor areas (supplementary motor area and dorsolateral prefrontal cortex) and reduced hyperactivity of the lentiform nucleus (augmented preoperatively). Pallidal (GPi) and subthalamic (STN) stimulation also increase activation of premotor areas but decrease activation of primary motor area. Suppression of unilateral tremor with thalamic stimulation is associated with a reduction in cerebellar blood flow. These main findings are in keeping with the general notion that increased activity in the STN GPi projection is directly implicated in the pathophysiology of PD. Surgical blockage of these output nuclei leads to partial restoration of cortical physiology.

Adult↗

Does sex influence the relation between symptoms and neurocognitive functions in schizophrenia?

OBJECTIVE: A secondary analysis of our data to investigate if sex influences the specificity of the relationship between each of the 3 clinical syndromes (i.e., reality distortion, disorganization and psychomotor poverty) in schizophrenia and the neurocognitive functions that are thought to represent regional brain functions. PATIENTS AND DESIGN: Fifty-seven male and 30 female patients with a DSM-III-R diagnosis of schizophrenia were rated on the Scale for Assessment of Negative Symptoms and the Scale for Assessment of Positive Symptoms to derive scores for psychomotor poverty, disorganization, and reality distortion syndromes. All subjects completed a battery of neuropsychological tests purported to assess functioning of left temporal, right temporal, left basal frontal, right basal frontal, and dorsolateral prefrontal cortex. RESULTS: Correlation coefficients between syndrome scores and neuropsychological measures showed only word fluency (left frontal functioning) to have a statistically significant association with psychomotor poverty in women (p < 0.01). This relation was specific to psychomotor poverty syndrome. No relations between neurocognitive measures and symptoms were seen in men. CONCLUSIONS: The lack of specific relations between symptom dimensions in schizophrenia may be influenced by the fact that the neuronal circuitry associated with particular symptom dimensions may differ in men and women.

Adult↗

Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives.

Schizophrenia patients and their relatives have saccadic abnormalities characterized by problems inhibiting a response. The dorsolateral prefrontal cortex and its associated circuitry ostensibly mediate inhibition and support correct delayed response performance. In this context, two components of delayed response task performance are of interest: memory saccade metrics and error saccades made during the delay. To evaluate these variables, an ocular motor delayed response task was presented to 23 schizophrenia patients, 25 of their first-degree biological relatives, and 19 normal subjects. The measure that best differentiated groups was an increased frequency of error saccades generated during the delay by schizophrenia subjects and relatives. Decreased memory saccade gain also characterized patients and relatives. The similar pattern of results demonstrated by the patients with schizophrenia and their relatives suggests that performance on ocular motor delayed response tasks, either alone or in combination with other saccadic variables, may provide useful information about neural substrates associated with a liability for developing schizophrenia.

Adult↗

Saccadic inhibition among schizotypal personality disorder subjects.

Schizotypal personality disorder (SPD) is theoretically part of the schizophrenia spectrum both clinically and neurobiologically. A liability for developing schizophrenia may be associated with dysfunction of dorsolateral prefrontal cortex (DLPFC) and its cortical and/or subcortical circuitry. If so, abnormalities on tasks associated with DLPFC functioning among SPD subjects would support the thesis that SPD is neurobiologically related to schizophrenia. Antisaccade and ocular motor delayed response performance, both of which are ostensibly supported by DLPFC circuitry, were assessed among 29 SPD, 17 schizophrenia, and 25 normal subjects. Generally, the SPD subjects' performance was more similar to normal than to schizophrenia groups. There was evidence, however, for inhibition abnormalities in a subgroup of SPD subjects. Antisaccade performance identified more SPD subjects as "abnormal" than delayed response measures.

Adult↗

[Executive dysfunction in Huntington's disease].

INTRODUCTION: In the early stages of Huntington s disease (HD), there is selective vulnerability of the medium-sized spinous cells of the striate nucleus. These cells are connected with the dorsolateral prefrontal cortex, which is an area involved in cognitive processes concerning attention and executive function, forming part of one of the cortico-striatal circuits. OBJECTIVE: To analyze and interpret the executive dysfunction of a group of patients with HD at a moderately advanced stage. PATIENTS AND METHODS: We evaluated 16 patients and controls. Three clinical scales were used: the motor section of the UHDRS, the independence scale and the total functional capacity scale. For cognitive evaluation we used the study protocol of the Core Assessment Program for Intracerebral Transplantation for HD (CAPIT-HD). RESULTS: The patients with EH showed significant deterioration on the tests to evaluate cognitive function, attention and working memory. There were only two exceptions, the WEST and the direct order digit span. CONCLUSIONS: Patients with HD have executive dysfunction, probably due to dysfunction of the cortico-striatal circuits. We therefore agree with the proposal that fronto-striatal cognitive dysfunction is the most suitable name for the cognitive deterioration seen in this condition.

Adult↗

[Investigation of the dopamine dysregulation hypothesis of schizophrenia with neuroimaging techniques].

The most elaborated biochemical concept of schizophrenia is the dopamine hypothesis. However, this classical theory is based on indirect observations. It has recently become possible to study this theory directly by means of advanced functional neuroimaging techniques, the development of specific radioligands and study protocols that are eligible to monitor dynamic changes in the neurotransmitter systems. According to the early concept, the essence of schizophrenia is the hyperactivity of the dopamine system. Nevertheless, this idea has gone through many modifications. In accordance with the modified dopamine hypothesis, the cognitive deficit and negative symptoms are related to the hypoactivity of the dorsolateral prefrontal cortex while the acute phases of the disease associates with hyperactivity of the ventral striatal elements of the dopaminergic system. Between these dysfunctions there is causality via their exuberant connections. Beyond that, the interactions between the prefrontal and striatal anomalies implicate the involvement of other neurotransmitters than dopamine. Observations from model psychosis induced by N-methyl-D-aspartate antagonists and in vivo neuroimaging investigations in humans support primarily the role of glutamatergic system. Our developing knowledge about the neurochemical mechanism of schizophrenia can significantly affect therapeutic strategies as well.

Amphetamine↗

[Panic disorder and transcranial magnetic stimulation].

Transcranial magnetic stimulation (TMS) has been tried in some Anxiety Disorders (Obsessive-compulsive disorder and Posttraumatic Stress Disorder) with different results. We present a pilot study including three Panic Disorder patients. The subjects who were enrolled had a history of the disease for at least 1 year and they had unsuccessfully followed psychotherapy and pharmacological treatment. The patients received 10 sessions during two weeks; each session lasted 30 trains of 60 seconds at a frequency of 1 Hz, on the right dorsolateral prefrontal cortex, at 110% of the motor threshold. All three patients experienced a modest and partial symptom improvement that did not seemed to be clinically relevant. Two patients accepted to participate in a TMS second phase, where the previous stimulation parameters were alternated with an application of 30 trains of 20 Hz during 2 seconds on the left prefrontal cortex. This alternate application of high and low frequency TMS in each session was also well tolerated, but failed to produce additional improvement. In addition to presenting these three cases, we emphasize some features concerning the neurobiological basis of the anxiety disorders and we connect them to the previously described TMS neurophysiological actions in order to justify further investigation.

Adult↗

[Brain imaging and mobility in Parkinson's disease].

Numerous abnormalities of motor function have been identified in Parkinson's disease and functional imaging methods have given us a better understanding of underlying mechanisms. An underactivity of some frontal areas, in particular the supplementary motor area and the dorsolateral-prefrontal cortex, has been found in several studies. The activity of these areas increases when motor function improves following administration of dopaminergic drugs or functional neurosurgery. The dysfunction of the basal ganglia-thalamo-cortical loops in Parkinson's disease and in particular the excess of inhibition of the thalamo-cortical pathway by the internal pallidum is likely to be involved in the abnormal activity of the cortical areas. An excess of activation has been demonstrated in other areas and is probably compensatory.

Basal Ganglia↗

Quantitative PET scan findings in carbon monoxide poisoning: deficits seen in a matched pair.

Quantitative positron emission tomography (PET) was utilized to establish the degree and localization of central nervous system dysfunction in 2 adult patients 3 years status postchronic carbon monoxide poisoning. The individual PET scans were compared against a composite scan made up of 32 normals using a z transformation statistical parametric map. Neuropsychological findings indicated marked anterior frontal lobe syndrome in the context of far-above-average intelligence, memory, and language. They also showed manifest frontal symptoms in activities of daily living that resulted in vocational disability in each case. PET analysis revealed substantially decreased metabolism in the orbitofrontal and dorsolateral prefrontal cortex as well as in areas of the temporal lobe for each individual. Individual scans were very similar and consistent with patient's presenting symptoms, and changed life circumstances. This report represents the first quantitative functional neuroimaging study relevant to carbon monoxide poisoning.

Clinical Conference↗

[Cognitive functions of the frontal lobe].

INTRODUCTION AND DEVELOPMENT: One way to divide the different regions of the frontal lobe is according to its connections with the thalamic regions. Each of these regions, with their own particular cytoarchitecture, phylogeny and ontogeny, are also involved in distinct cognitive functions. The dorsolateral prefrontal cortex enables plans of action to be developed and executed, and working memory, which is needed for most cognitive processing, is the driving force behind what we call the executive functions. The orbital cortex and its subcortical connections make up a circuit that allows attention to be held and directed through a series of inhibitory mechanisms; this in turn prevents interference by stimuli that are irrelevant for a particular purpose. Finally, the cingulate cortex plays a part in initiating actions, in the intentionality of responses and in focusing attention. CONCLUSIONS: A deeper knowledge of the mechanisms behind the workings of the frontal lobe can explain the clinical pictures that are observed in many of the pathologies that appear during infancy, such as attention deficit hyperactivity disorder.

Animals↗

The role of executive functioning in spontaneous confabulation.

OBJECTIVE: To follow the recovery course of a patient who exhibited an amnesic-confabulatory syndrome in conjunction with severe executive dysfunction in the first week following bithalamic infarction. BACKGROUND: Previous studies have shown that spontaneous confabulation originates from the combination of amnesia and executive dysfunction and that the degree of confabulation is determined by the degree of executive dysfunction. However, a few studies have also reported a dissociation between spontaneous confabulation and executive dysfunction. Therefore, the role of executive functioning in spontaneous confabulation is presently unclear. METHOD: Clinical examinations, magnetic resonance imaging (MRI), and cognitive and behavioral assessments with a focus on executive functions were conducted within the first week poststroke and after 6 months. RESULTS: MRI showed a bithalamic infarction involving the territory of the paramedian arteries predominantly affecting the dorsomedial and intralaminar nuclei of the thalami. Disappearance of spontaneous confabulation paralleled a specific recovery in mental flexibility, whereas all other executive components and long-term memory remained severely impaired at 6 months poststroke. CONCLUSIONS: Our case study provides additional evidence that mental flexibility, but not executive functioning in general, is a prerequisite for spontaneous confabulation. Direct or indirect functional deactivation of dorsolateral prefrontal cortex may be necessary for the development of spontaneous confabulation.

Amnesia↗

[Working memory in basic learning processes].

INTRODUCTION AND DEVELOPMENT: Working or operative memory is considered to be a distinctive element of executive functioning. Nowadays, thanks to neuroimaging studies, it is known that the dorsolateral prefrontal cortex plays a crucial role in working memory. It has been observed that during the intervals when information is being retained, intense and persistent activity is going on in the region, as shown by the delayed response times. Working memory is fundamental for the analysis and synthesis of information, the retention of data needed to perform a particular mental process, carrying out priming (impression in memory of something that has been experienced, such as words, objects or events, for example), carrying out pre-functional tutoring activities and post-functional monitoring. CONCLUSIONS: Disorders affecting the fundamental mechanisms of working memory will give rise to a dysfunction that will exert an influence on innumerable formal academic learning processes such as difficulty in focusing attention, difficulty in inhibiting irrelevant stimuli, difficulty in recognising priority patterns, inability to recognise hierarchies and the meaning of stimuli (analysis and synthesis), problems in establishing an intention, and difficulty in recognising and selecting the goals that are best suited to solving a problem. It will also involve the impossibility to establish a plan to achieve goals, inability to analyse the activities required to accomplish an objective and difficulties in carrying out a plan, since it becomes impossible to monitor or modify the task to fit the original plans.

Learning↗

Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the literature pertaining to rapid-rate repetitive transcranial magnetic stimulation (rTMS) compared with sham therapy for the treatment of a major depressive episode in order to arrive at qualitative and quantitative conclusions about the efficacy of rapid-rate rTMS. METHODS: MEDLINE, the Cochrane Library, the metaRegister of Controlled Trials and abstracts from scientific meetings were searched for the years 1966 until July 2003. The search terms "transcranial magnetic stimulation" and "transcranial magnetic stimulation AND depression" were used. Eighty-seven randomized controlled trials investigating the efficacy of rTMS were referenced on MEDLINE. Nineteen of these involved treatment of a major depressive episode, and these were reviewed. Six met more specific inclusion criteria including the use of rapid-rate stimulation, application to the left dorsolateral prefrontal cortex, evaluation with the 21-item Hamilton Rating Scale for Depression (HAM-D) and use of an intent-to-treat analysis. Scores on the 21-item HAM-D after treatment and standard deviations were extracted from each article for treatment and control subjects. A random-effects model was chosen for the meta-analysis, and the weighted mean difference was used as a summary measure. RESULTS: Six studies that met the inclusion criteria were identified and included in the meta-analysis. Two of these reported a significantly greater improvement in mood symptoms in the treatment versus the sham group. When combined in the meta-analysis, the overall weighted mean difference was -1.1 (95% confidence interval -4.5 to 2.3), and the results of a test for heterogeneity were not significant (chi2(5) = 5.81, p = 0.33). CONCLUSIONS: This meta-analysis suggests that rapid-rate rTMS is no different from sham treatment in major depression; however, the power within these studies to detect a difference was generally low. Randomized controlled trials with sufficient power to detect a clinically meaningful difference are required.

Major Depressive Disorder↗

Repetitive transcranial magnetic stimulation in a patient suffering from depression and rheumatoid arthritis: evidence for immunomodulatory effects.

Repetitive transcranial magnetic stimulation (rTMS) has been suggested as antidepressive treatment strategy. The mechanism of action by which the antidepressive effect is brought about remains unclear at present. Here, we report findings in a patient suffering from recurrent major depression and rheumatoid arthritis. Improvement of depressive symptoms during 20 Hz rTMS of the left dorsolateral prefrontal cortex was repeatedly associated with a systemic inflammatory reaction, suggesting that rTMS induced an immunomodulatory effect.

Aged↗

[Frontal dysfunction in idiopathic Parkinson's disease].

INTRODUCTION: In his description of the disease in his original work, James Parkinson claimed that the 'senses remained intact', but later reports began to identify cognitive impairment that ranged from dementia to barely identifiable subclinical deteriorations. Research carried out in recent decades has revealed that cognitive disorders form part of the clinical symptoms of Parkinson's disease (PD) and point to the frontal lobes as being the most affected areas; a great deal of controversy, however, still surrounds their definition, epidemiology and pathology. AIM: To determine and classify the frontal deficits associated to this disease and to relate this cognitive performance with certain characteristics of the disease. SUBJECTS AND METHODS: The sample utilised in the study was made up of 222 subjects divided into two groups according to their diagnosis: 111 subjects with idiopathic PD and 111 control subjects. The neuropsychological examination was performed using the Frontal Assessment Battery, the copy of the Rey-Osterrieth complex figure and the digit test for determining frontal functioning. RESULTS AND CONCLUSIONS: We prove the existence of a frontal dysfunction that is characterised by impaired working memory, with visuospatial and executive dysfunction, which suggests greater involvement of the dorsolateral prefrontal cortex and cingulate. According to our findings, because working memory and visuospatial functioning are correlated to the motor status and the time elapsed since the onset of the disease, they could share the same underlying neuroanatomical foundations--the nigrostriatal denervation. This is not the case of executive function, which was not found to be related to the characteristics of the disease under study.

Cognition Disorders↗

Probing cortical dopamine function in schizophrenia: what can D1 receptors tell us?

Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. Positive symptoms may be related to excessive dopamine (DA) function, as suggested by the common antidopaminergic properties of antipsychotic medications, which are most effective at treating positive symptoms. Negative symptoms and impairment in higher cognitive functions are thought to be related to a dysfunction of the dorsolateral prefrontal cortex (DLPFC), possibly related to inappropriate stimulation of D1 receptors. In the last few years we have clearly demonstrated excess subcortical DA transmission and now have indirect evidence for cortical dopamine deficit. We studied 16 drug free patients with schizophrenia (7 drug naïve and 9 previously treated) and 16 matched controls, using positron emission tomography (PET) and [(11)C]NNC 112, a novel radiotracer for PET imaging of the D1 receptor, and the n-back task, a test of working memory. We observed a significant upregulation in D1 binding in the DLPFC in patients with schizophrenia compared to controls. This increase was present in both drug naïve and previously treated patients and was regionally selective. Furthermore, the increase was correlated with poor performance on the n-back task (r(2)=0.45, p=0.004). This upregulation of D1 receptors might be secondary to a sustained deficit in prefrontal DA function, as postmortem studies revealed deficits in DA innervation in the prefrontal cortex in schizophrenia.

Journal Article↗