M F Glabus

Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression.

PURPOSE Transcranial magnetic stimulation (TMS) has been used for over a decade to investigate cortical function. More recently, it has been employed to treat conditions such as major depression. This study was designed to explore the effects of differential treatment parameters, such as stimulation frequency. In addition, the data were examined to determine whether a change in connectivity occurred following TMS. METHOD Fifteen patients with major depression were entered into a combined imaging and treatment experiment with single photon emission computed tomography (SPECT) and repetitive transcranial magnetic stimulation (rTMS) over left dorso-lateral prefrontal cortex (DLPFC). Brain perfusion during a verbal fluency task was compared between pre- and poststimulation conditions. Patients were then treated with 80% of motor threshold for a total of 10 days, using 5000 stimuli at 5, 10 or 20 Hz. Tests of cortical excitability and neuropsychological tests were done throughout the trial. FINDINGS Patients generally improved with treatment. There was no perceptible difference between stimulation frequencies, which may have reflected low study power. An increase in rostral anterior cingulate activation after the treatment day was associated with increased functional connectivity in the dorso-lateral frontal loop on the left and the limbic loop on both sides. No noticeable deterioration in neuropsychological function was observed. CONCLUSION TMS at the stimulation frequencies used seems to be safe over a course of 5000 stimuli. It appears to have an activating effect in anterior limbic structures and increase functional connectivity in the neuroanatomical networks under the stimulation coil within an hour of stimulation.

Cognitive brain potentials and regional cerebral blood flow equivalents during two- and three-sound auditory "oddball tasks".

Ten healthy volunteers were examined with single photon emission tomography and 99mTc-exametazime. They were studied on 2 occasions, during a 2- and a 3-sound auditory discrimination (oddball) task. Twenty healthy volunteers were used as controls, studied once at rest. During the 2-tone task there was a bilateral posterior (occipito-) temporal and medial frontal activation, a left pericentral increase, and posterior cingulate suppression. During the 3-sound task activation was again found in posterior (occipito-) temporal, medial frontal cortex, left pericentral, with a small non-significant reduction in posterior cingulate uptake. Compared with the 2-tone task, there was a trend towards higher activity in left medial frontal, right posterior temporal and posterior cingulate cortex in the 3-sound task. P3b amplitudes were negatively correlated with posterior cingulate tracer uptake during both tasks. Positive correlations with P3b amplitudes were found in various frontal and temporal regions. These results are consistent with more invasive localisation studies of P3b. Posterior cingulate cortex appears to be inhibited during the oddball tasks, the more so, the more restricted the range of stimuli, and the greater the task-related recruitment of neurones (P3b amplitude). As expected from its more frontal distribution, P3a amplitude was positively correlated with anterior cingulate tracer uptake, and negatively correlated with temporal cortical activity.

Reduction of cingulate gray matter density in poor outcome bipolar illness

Structural brain abnormalities are associated with poor outcome unipolar depressive disorder. Gray matter density can be assessed with an automated, operator independent analysis (SPM99). We thus compared 11 poor outcome bipolar patients with 15 age-, sex- and IQ-matched healthy volunteers with a standard neuropsychological examination and an Elscint 2.0 Tesla MRI scanner. At the time of examination, patients were neither hypomanic nor significantly depressed, but were significantly impaired on the McGlashan scale. Their memory function was characterized by reduced performance in the California verbal learning and digit-symbol substitution tests. Statistical parametric mapping revealed abnormal gray matter density, mainly in fronto-limbic cortex, but particularly widespread in cingulate cortex. Although causality of these changes is difficult to resolve, the results offer useful insights into the neural correlates of severe bipolar disorder.

Increased cortical inhibition in depression: a prolonged silent period with transcranial magnetic stimulation (TMS).

BACKGROUND Motor slowing in depression may be associated with a relative dopaminergic (DA) deficit. Bradykinesia in Parkinsons syndrome is associated with an abnormally short silent period (SP) using transcranial magnetic stimulation (TMS). We hypothesized that depression would also be associated with a short SP. METHODS Sixteen patients with DSM-IV depression and 19 matched controls participated. SPs were elicited by exercising the contralateral abductor policis brevis (APB) during TMS. RESULTS The SP was significantly increased in the patient group. No correlation was found between SP and depression score. CONCLUSION A long SP suggests increased motor cortical inhibition in depression. This finding is inconsistent with the hypothesis of behavioural motor slowing in depression being associated with Parkinsonian-like mechanisms including the dopaminergic deficit. There is a need for studies incorporating larger patient groups to investigate potential correlations between SP and depression indices.

Oral Amino Acid Load Mimicking Hemoglobin Results in Reduced Regional Cerebral Perfusion and Deterioration in Memory Tests in Patients with Cirrhosis of the Liver

This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67–94) μmol/L to 105 (98–112) μmol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.

Methodological considerations in measurement of the P300 component of the auditory oddball ERP in schizophrenia

Twenty-three schizophrenic patients and 26 age-matched control subjects were studied using the P300 recorded during the auditory oddball task, with counting. Our aim was to assess the most suitable method of measurement and analysis of P300 amplitude and latency for use in clinical studies of schizophrenia. The effect of high-pass filtering, peak definition method and recording electrode site were all investigated. We have developed a technique, based on a least-mean-squares approximation to data, which seems particularly well suited to dealing with multi-peak P300 complexes. We have also investigated the spectral composition of the P300 and have found some evidence to support a proposed 2-frequency model of the P300 complex.

Correlation of regional cerebral blood flow equivalents measured by single photon emission computerized tomography with P300 latency and eye movement abnormality in schizophrenia.

Single photon emission tomography with the intravenous blood flow marker 99mTc‐exametazime was carried out in 14 acutely ill drug‐free schizophrenic patients from whom P300 event‐related potential, smooth eye pursuit eye tracking and verbal fluency were measured within a few days of scanning. Smooth pursuit eye movement abnormality correlated significantly with abnormal tracer uptake in superior pre‐frontal cortex on the right and left and inferior pre‐frontal cortex on the left. Abnormal eye movement was also associated with higher tracer uptake in left anterior cingulate and left posterior cingulate. P300 latency was significantly correlated with higher tracer uptake in left superior pre‐frontal and left parietal regions. Verbal fluency performance was negatively correlated with tracer uptake in left frontal region. Eye tracking abnormality in schizophrenia is associated with bilateral frontal lobe disturbance and P300 latency increase with left‐sided frontal and temporoparietal dysfunction. There was, however, a significant inverse relation between eye tracking abnormalities and abnormal perfusion in the left anterior cingulate region.

Postexercise motor evoked potentials in depressed patients, recovered depressed patients, and controls

Article abstract We hypothesized that impaired postexercise motor evoked potential (MEP) facilitation in depressed patients would reverse with recovery from depression. Transcranial magnetic stimulation and exercise of the thenar muscles were used to examine the 10 controls, 10 medicated depressed patients, and 10 medicated recovered patients. Depressed patients showed reduced mean postexercise facilitation compared to both controls (p = 0.005) and recovered patients (p = 0.012). Controls and recovered patients had similar mean postexercise MEPs (p = 0.45). This is consistent with other evidence of reversibility of abnormal findings following recovery from depression.

The effect of different high-pass filter settings on peak latencies in the event-related potentials of schizophrenics, patients with Parkinson's disease and controls

Eighteen schizophrenic patients, 16 patients with idiopathic Parkinsons disease, and the same numbers of age, sex and education matched controls were examined with oddball experiments for the generation of P3. Individual averages were high-pass filtered at different cut-off frequencies with single-pole digital filters with equivalent analogue Butterworth filter profiles. The purpose of this procedure was to simulate analogue high-pass filters used in clinical studies from different centres and to examine their potential effect on group differences. Increasing high-pass filters resulted in a phase lead for all peaks examined (N1, P2, N2, P3). The only group differences were found for P3, which showed a greater phase lead in controls than in the patient groups, usually resulting in a more pronounced group difference. Similar wave forms and filter properties could be modelled by synthetic wave forms consisting of sine waves of different frequencies.

Executive function and uptake of 99mTc-exametazime shown by single photon emission tomography after oral idazoxan in probable Alzheimer-type dementia.

Abstract Preliminary reports suggest improved executive function in patients with lobar dementia after treatment with single doses of the alpha2 adrenoceptor antagonist, idazoxan. The potential for use in probable Alzheimer-type dementia prompted the present study. Fifteen patients with probable Alzheimer-type dementia were examined twice with neuropsychological measures and 14 also with single photon emission tomography (SPET) after a single double blind oral administration of 40 mg idazoxan or placebo in a balanced cross-over design. Brain perfusion maps were spatially transformed into standard stereotactic space and compared pixel-by-pixel. A parametric analysis was used to examine the relationship between the drug effect, verbal fluency and brain perfusion. Two to 3 h after idazoxan, measures of reaction time, Stroop test, category fluency and anxiety were unchanged. Verbal fluency (letter) and spatial working memory were impaired and performance on the Tower of London test in a sub-set of patients showed a trend to impairment in the idazoxan condition. Idazoxan produced a modest relative activation in left thalamus and inferior occipital cortex; decreases occurred in inferior anterior cingulate and left insular cortex. There were significant correlations on both days between measures of fluency and brain perfusion in left lateral prefrontal cortex. The reduced performance with idazoxan was directly correlated with reduced perfusion in left lateral prefrontal cortex, supporting an important interaction between drug and task perfomance. The imaging component of the study therefore suggested that activation of frontal networks is necessary for performing fluency tasks in Alzheimer-type dementia. Brain networks involving prefrontal cortex are the locus for the primary cognitive effects of noradrenergic drugs. The direction of the effect of any dose of agonist or antagonist may depend critically upon the age and pathology of the experimental subjects and the relationship between performance, noradrenergic drive and task difficulty.