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hyperactivity disorder: A diffusion tensor imaging study in adult patients
e26
Society Proceedings / Clinical Neurophysiology 120 (2009) e9–e88
Results: Until a significant shortened duration of the ISP in ADHD patients (ADHD: 17.1 ± 4.0 ms; control-group: 22.8 ± 6.6 ms; p = 0.002) was found, no further significant differences between patients and normal controls could be detected, e.g. the CSP, the latency of the ISP, SICI, ICF and LICI were undisturbed. In addition, we revealed a significantly negative correlation between the duration of the ISP and clinical symptoms showing remaining hyperactive behaviour (CAARS-subscore-B), whereas the correlation between the duration of the ISP and inattentive symptoms (CAARS-subscore-E) was not significant. The group of 16 medicated patients (MPH – mean dosage: 0.44 ± 0.22 mg/kg/d) showed a significant prolongation of the duration of ISP compared with their premedication state (22.2 ± 6.5 ms // 17.4 ± 4.5 ms; p = 0.007). Discussion: Our study in adults with ADHD is one of the first using the same TMS protocol, which allowed us to detect disturbances of the inter- and intra-hemispheric inhibition in ADHD children before. Contrary to that and with exception of the ISP, we did not find impairments of cortical motor excitability in our adult ADHD patients compared to age- and gender-matched normal control subjects. Interestingly, exclusively the duration of the ISP was shortened similar to the results in children, correlated with remaining hyperactive symptoms and was normalized on the partial dopamine agonist MPH [Höppner et al., 2008]. Pathophysiologically, a partly normalization of a dopamine-mediated deficit of cortical motor inhibition through synaptic maturation processes could be assumed as one possible reason, whereas the still disturbed inter-hemispheric inhibition in our patients could explain the remaining hyperactive behaviour in ADHD adults.
Table 1
Gender (m/f) Age (years) IQ WURS BADDS TOVA
ADHD patients mean ± SD
Controls mean ± SD
P value
11 / 9 31.0 ± 9.9 110.4 ± 8.6 116.6 ± 36.2 71.4 ± 24.8 4.4 ± 6.0
11 / 9 31.3 ± 9.2 111.3 ± 8.5 55.3 ± 19.3 13.5 ± 10.1 1.9 ± 2.0
n.s. n.s. n.s. <0.001 <0.001 <0.001
References Barkley RA et al. J Abnorm Psychol 2002. Biederman J et al. Am J Psychiatry 2000. Lahey BB et al. Biol Psychiatry 1994. Buchmann J et al. Biol Psychiatry 2007. Buchmann J et al. Clin Neurophysiol 2003. Höppner J et al. J Neural Transm 2008.
Fig. 1.
doi:10.1016/j.clinph.2008.07.056
58. White matter abnormalities in attention-deficit/hyperactivity disorder: A diffusion tensor imaging study in adult patients—A. Konrad 1, T.F. Dielentheis 1, D. El Masri 1, M. Bayerl 1, G. Winterer 2, T. Bauermann 3, G. Vucurevic 3, P. Stoeter 3 (1 Johannes GutenbergUniversität Mainz, Klinik für Psychiatrie und Psychotherapie, Mainz, Germany, 2 Heinrich-Heine-Universität Düsseldorf, Klinik für Psychiatrie, Düsseldorf, Germany, 3 Johannes GutenbergUniversität Mainz, Institut für Neuroradiologie, Mainz, Germany) Objective: Structural and functional neuroimaging studies of subjects with attention-deficit/hyperactivity disorder (ADHD) demonstrated abnormalities primarily in the frontal-striatal circuitry, but also in the corpus callosum, cerebellum, and cortical regions. However, most structural studies were based on volumetric measurements and have been conducted in children. Therefore, the aim of this study was to investigate changes of white matter integrity in adult subjects with ADHD(1). Methods: n = 20 (11 males) ADHD patients and 20 age- and gender matched healthy control subjects underwent a detailed clinical interview as well as neuropsychological investigation of intelligence, memory, attention, psychomotor performance and executive functioning. Diffusion tensor imaging (DTI) was performed and 10 white matter regions of interest (ROIs) were chosen. Mean fractional
Fig. 2.
anisotropy (FA) in each ROI was then calculated and compared between groups (Figs. 1 and 2). Results: Typical group differences in ADHD measures were found. ADHD patients showed reduced FA in all ROIs except in the corpus callosum. The difference was significant (P = 0.0006) in the left inferior longitudinal fasciculus. Conclusion: We were able to demonstrate primarily left temporal white matter changes in adult ADHD patients. Reduced anisot-
Society Proceedings / Clinical Neurophysiology 120 (2009) e9–e88
ropy in the left temporal lobe may be linked to disturbed auditory– linguistic functioning in ADHD patients. References Ashtari M et al. Biol Psychiatry 2005;57:448–55. Makris N et al. Cereb Cortex 2007;57:448–55 [epub ahead of print]. Seidman LJ et al. Biol Psychiatry 2005;57:1263–72. Valera EM et al. Biol Psychiatry 2007;61:1361–9. doi:10.1016/j.clinph.2008.07.057
59. Neurophysiological evidence of corticospinal tract dysfunction in Wilson’s disease—P. Günther 1, W. Hermann 2, A. Wagner 1,2 (1 Universität Leipzig, Neurologie, Leipzig, Germany, 2 Paracelsusklinik Zwickau, Neurologie, Zwickau, Germany) Introduction: Wilson’s disease is a rare autosomal recessive disorder of hepatic copper transport leading to a biliary excretion inhibition of copper. Overload of the metal mainly in liver and basal ganglia leads to hepatic, but also to extrapyramidal motor clinical symptoms. However, involvement of the corticospinal system is hardly known. Methods: To study corticospinal tract dysfunction in Wilson’s disease, motor-evoked potentials (MEP) were performed in 42 patients (14 with a non-neurological and 28 with a neurological form) with Wilson’s disease undergoing long-term treatment. Fwave method was used to determine the central motor latency of the corticospinal pathway. Results were determined and compared with laboratory reference values of a group of 40 healthy persons. Results: In more than half of the patients with a neurological form of Wilson’s disease, abnormalities with delayed latencies and significant reductions of MEP amplitudes occurred. However, also in patients with the non-neurological form prolonged latencies were found. There was no evidence for cerebrovascular nor major spinal disease. Discussion: MEP are useful in monitoring and differential diagnosis of patients with Wilson’s disease. They might predict a deterioration of a non-neurological into a neurological form of this complex disorder. doi:10.1016/j.clinph.2008.07.058
e27
may be represented by absolute glutamate concentrations measured with magnetic resonance spectroscopy (MRS; [Knutson, 2001]). (4) An interaction of dopaminergic and glutamatergic neurotransmission has so far not been imaged in humans. A correlation between the activity of the ventral striatum (BOLD contrast during reward processing) and glutamate concentration in the anterior cingulate cortex in healthy subjects is hypothesized. Methods: Twenty-two healthy subjects (age 19–46 years) participated in a combined fMRI and MRS experiment. In a reward-task similar to Knutson’s paradigm [Knutson, 2001], participants could win or lose 1 Euro in approx. 160 trials; contrast images of positive anticipation against anticipation of neutral trials were used in further analysis. To ensure that the observed activation was located in the ventral striatum, we used a voxel mask (296 voxels) from a probabilistic MNI atlas [Fox, 2002,] at a threshold of 0.75 probability. MRS was performed in the same session with fMRI. MR spectra were acquired using PRESS optimized for glutamate detection (TE = 80 ms, TR = 3 s, n = 128 (Knutson, 2001)) from (1) the left hippocampus (HC; 2 2 1.2 cm3), and (2) the anterior cingulate cortex (ACC; 2.5 4 2 cm3). Results: fMRI of the ventral striatum. In healthy subjects positive anticipation led to robust bilateral activation in the ventral striatum (peak voxel at (x, y, z) = 18, 6, 10; T = 4.48, p < 0.001, corrected). Association of ventral striatum activation with glutamate. Within the region of interest, multiple regression analysis shows activation in a cluster of 73 voxels on the left side (peak voxel at (x, y, z) = 18, 16, 6; T = 2.34, P < 0.05, uncorrected) and 23 voxels on the right side (peak voxel at (x, y, z) = 8, 12, 6; T = 2.12, P < 0.05, uncorrected) to be negatively correlated with the concentration of glutamate in the ACC. No significant positive correlations were observed, and no significant correlations (positive or negative) were observed for the hippocampal glutamate concentration. The findings indicate that frontal glutamate may be related to the activation of the ventral striatum. Discussion: This association is compatible with the neuronal model of Carlsson (Carlsson, 1990), stressing a modulatory effect of cortical glutamate on the dopaminergic activity in the ventral striatum. Our results may indirectly visualize an interaction of dopaminergic and glutamatergic neurotransmission which would be highly relevant for schizophrenia research. References
60. Cortical glutamate is linked to reward-related ventral striate activity – a combined fMRI and 1H-MRS study—J. Reuter 1, N. Klein 1, M. Voss 1, T. Dembler 1, Y. Gudlowski 1, A. Heinz 1, J. Gallinat 1, R. Brühl 2, F. Schubert 2, F. Seifert 2 (1 Charité, Psychiatrische Universitätsklinik, Berlin, Germany, 2 Physikalisch Technische Bundesanstalt, Berlin, Germany) Introduction: (1) Processing of rewarding stimuli is associated with increased firing rate of dopamine neurons in the ventral striatum, a core region of the brain reward system. Psychiatric diseases with dysfunctional reward behavior, like schizophrenia, are associated with abnormal dopaminergic neurotransmission and dysfunctional activation of the ventral striatum (Juckel, 2006). (2) A close interaction between dopamine and glutamate has been proposed to play an important role in reward processing and in the pathophysiology of schizophrenia [Carlsson, 1990]. (3) In humans, aspects of dopamine function may be reflected by the BOLD activity of the ventral striatum during presentation of rewarding stimuli [Juckel, 2006, 1990], and glutamatergic function
Juckel G. Neuroimage 2006;29:409–16. Carlsson M. Trends Neurosci 1990;13:272–6. Knutson B. J Neurosci 2001;21:RC159. Schubert F. Neuroimage 2004;21:1762–71. Fox P. Nat Rev Neurosci 2002;3:319–21. Nielsen F. Neuroimage 2002;16. doi:10.1016/j.clinph.2008.07.059
61. Electrophysiological study in juvenile asymmetric segmental spinal muscular atrophy (Hirayama disease)—W. Dietrich 1, F. Erbguth 1, G. Berger 1, R. Gerlach 2, I. Bär 2, B. Schmid 1 (1 Klinikum Nürnberg, Klinik für Neurologie, Nürnberg, Germany, 2 Klinikum Nürnberg, Abteilung für Radiologie, Nürnberg, Germany) Hirayama disease (HD) is characterized by slowly progressive distal amyotrophy of upper limb, usually monolateral, occurring predominantly in young Asian men. The aetiology of HD is not well
Society Proceedings / Clinical Neurophysiology 120 (2009) e9–e88
Results: Until a significant shortened duration of the ISP in ADHD patients (ADHD: 17.1 ± 4.0 ms; control-group: 22.8 ± 6.6 ms; p = 0.002) was found, no further significant differences between patients and normal controls could be detected, e.g. the CSP, the latency of the ISP, SICI, ICF and LICI were undisturbed. In addition, we revealed a significantly negative correlation between the duration of the ISP and clinical symptoms showing remaining hyperactive behaviour (CAARS-subscore-B), whereas the correlation between the duration of the ISP and inattentive symptoms (CAARS-subscore-E) was not significant. The group of 16 medicated patients (MPH – mean dosage: 0.44 ± 0.22 mg/kg/d) showed a significant prolongation of the duration of ISP compared with their premedication state (22.2 ± 6.5 ms // 17.4 ± 4.5 ms; p = 0.007). Discussion: Our study in adults with ADHD is one of the first using the same TMS protocol, which allowed us to detect disturbances of the inter- and intra-hemispheric inhibition in ADHD children before. Contrary to that and with exception of the ISP, we did not find impairments of cortical motor excitability in our adult ADHD patients compared to age- and gender-matched normal control subjects. Interestingly, exclusively the duration of the ISP was shortened similar to the results in children, correlated with remaining hyperactive symptoms and was normalized on the partial dopamine agonist MPH [Höppner et al., 2008]. Pathophysiologically, a partly normalization of a dopamine-mediated deficit of cortical motor inhibition through synaptic maturation processes could be assumed as one possible reason, whereas the still disturbed inter-hemispheric inhibition in our patients could explain the remaining hyperactive behaviour in ADHD adults.
Table 1
Gender (m/f) Age (years) IQ WURS BADDS TOVA
ADHD patients mean ± SD
Controls mean ± SD
P value
11 / 9 31.0 ± 9.9 110.4 ± 8.6 116.6 ± 36.2 71.4 ± 24.8 4.4 ± 6.0
11 / 9 31.3 ± 9.2 111.3 ± 8.5 55.3 ± 19.3 13.5 ± 10.1 1.9 ± 2.0
n.s. n.s. n.s. <0.001 <0.001 <0.001
References Barkley RA et al. J Abnorm Psychol 2002. Biederman J et al. Am J Psychiatry 2000. Lahey BB et al. Biol Psychiatry 1994. Buchmann J et al. Biol Psychiatry 2007. Buchmann J et al. Clin Neurophysiol 2003. Höppner J et al. J Neural Transm 2008.
Fig. 1.
doi:10.1016/j.clinph.2008.07.056
58. White matter abnormalities in attention-deficit/hyperactivity disorder: A diffusion tensor imaging study in adult patients—A. Konrad 1, T.F. Dielentheis 1, D. El Masri 1, M. Bayerl 1, G. Winterer 2, T. Bauermann 3, G. Vucurevic 3, P. Stoeter 3 (1 Johannes GutenbergUniversität Mainz, Klinik für Psychiatrie und Psychotherapie, Mainz, Germany, 2 Heinrich-Heine-Universität Düsseldorf, Klinik für Psychiatrie, Düsseldorf, Germany, 3 Johannes GutenbergUniversität Mainz, Institut für Neuroradiologie, Mainz, Germany) Objective: Structural and functional neuroimaging studies of subjects with attention-deficit/hyperactivity disorder (ADHD) demonstrated abnormalities primarily in the frontal-striatal circuitry, but also in the corpus callosum, cerebellum, and cortical regions. However, most structural studies were based on volumetric measurements and have been conducted in children. Therefore, the aim of this study was to investigate changes of white matter integrity in adult subjects with ADHD(1). Methods: n = 20 (11 males) ADHD patients and 20 age- and gender matched healthy control subjects underwent a detailed clinical interview as well as neuropsychological investigation of intelligence, memory, attention, psychomotor performance and executive functioning. Diffusion tensor imaging (DTI) was performed and 10 white matter regions of interest (ROIs) were chosen. Mean fractional
Fig. 2.
anisotropy (FA) in each ROI was then calculated and compared between groups (Figs. 1 and 2). Results: Typical group differences in ADHD measures were found. ADHD patients showed reduced FA in all ROIs except in the corpus callosum. The difference was significant (P = 0.0006) in the left inferior longitudinal fasciculus. Conclusion: We were able to demonstrate primarily left temporal white matter changes in adult ADHD patients. Reduced anisot-
Society Proceedings / Clinical Neurophysiology 120 (2009) e9–e88
ropy in the left temporal lobe may be linked to disturbed auditory– linguistic functioning in ADHD patients. References Ashtari M et al. Biol Psychiatry 2005;57:448–55. Makris N et al. Cereb Cortex 2007;57:448–55 [epub ahead of print]. Seidman LJ et al. Biol Psychiatry 2005;57:1263–72. Valera EM et al. Biol Psychiatry 2007;61:1361–9. doi:10.1016/j.clinph.2008.07.057
59. Neurophysiological evidence of corticospinal tract dysfunction in Wilson’s disease—P. Günther 1, W. Hermann 2, A. Wagner 1,2 (1 Universität Leipzig, Neurologie, Leipzig, Germany, 2 Paracelsusklinik Zwickau, Neurologie, Zwickau, Germany) Introduction: Wilson’s disease is a rare autosomal recessive disorder of hepatic copper transport leading to a biliary excretion inhibition of copper. Overload of the metal mainly in liver and basal ganglia leads to hepatic, but also to extrapyramidal motor clinical symptoms. However, involvement of the corticospinal system is hardly known. Methods: To study corticospinal tract dysfunction in Wilson’s disease, motor-evoked potentials (MEP) were performed in 42 patients (14 with a non-neurological and 28 with a neurological form) with Wilson’s disease undergoing long-term treatment. Fwave method was used to determine the central motor latency of the corticospinal pathway. Results were determined and compared with laboratory reference values of a group of 40 healthy persons. Results: In more than half of the patients with a neurological form of Wilson’s disease, abnormalities with delayed latencies and significant reductions of MEP amplitudes occurred. However, also in patients with the non-neurological form prolonged latencies were found. There was no evidence for cerebrovascular nor major spinal disease. Discussion: MEP are useful in monitoring and differential diagnosis of patients with Wilson’s disease. They might predict a deterioration of a non-neurological into a neurological form of this complex disorder. doi:10.1016/j.clinph.2008.07.058
e27
may be represented by absolute glutamate concentrations measured with magnetic resonance spectroscopy (MRS; [Knutson, 2001]). (4) An interaction of dopaminergic and glutamatergic neurotransmission has so far not been imaged in humans. A correlation between the activity of the ventral striatum (BOLD contrast during reward processing) and glutamate concentration in the anterior cingulate cortex in healthy subjects is hypothesized. Methods: Twenty-two healthy subjects (age 19–46 years) participated in a combined fMRI and MRS experiment. In a reward-task similar to Knutson’s paradigm [Knutson, 2001], participants could win or lose 1 Euro in approx. 160 trials; contrast images of positive anticipation against anticipation of neutral trials were used in further analysis. To ensure that the observed activation was located in the ventral striatum, we used a voxel mask (296 voxels) from a probabilistic MNI atlas [Fox, 2002,] at a threshold of 0.75 probability. MRS was performed in the same session with fMRI. MR spectra were acquired using PRESS optimized for glutamate detection (TE = 80 ms, TR = 3 s, n = 128 (Knutson, 2001)) from (1) the left hippocampus (HC; 2 2 1.2 cm3), and (2) the anterior cingulate cortex (ACC; 2.5 4 2 cm3). Results: fMRI of the ventral striatum. In healthy subjects positive anticipation led to robust bilateral activation in the ventral striatum (peak voxel at (x, y, z) = 18, 6, 10; T = 4.48, p < 0.001, corrected). Association of ventral striatum activation with glutamate. Within the region of interest, multiple regression analysis shows activation in a cluster of 73 voxels on the left side (peak voxel at (x, y, z) = 18, 16, 6; T = 2.34, P < 0.05, uncorrected) and 23 voxels on the right side (peak voxel at (x, y, z) = 8, 12, 6; T = 2.12, P < 0.05, uncorrected) to be negatively correlated with the concentration of glutamate in the ACC. No significant positive correlations were observed, and no significant correlations (positive or negative) were observed for the hippocampal glutamate concentration. The findings indicate that frontal glutamate may be related to the activation of the ventral striatum. Discussion: This association is compatible with the neuronal model of Carlsson (Carlsson, 1990), stressing a modulatory effect of cortical glutamate on the dopaminergic activity in the ventral striatum. Our results may indirectly visualize an interaction of dopaminergic and glutamatergic neurotransmission which would be highly relevant for schizophrenia research. References
60. Cortical glutamate is linked to reward-related ventral striate activity – a combined fMRI and 1H-MRS study—J. Reuter 1, N. Klein 1, M. Voss 1, T. Dembler 1, Y. Gudlowski 1, A. Heinz 1, J. Gallinat 1, R. Brühl 2, F. Schubert 2, F. Seifert 2 (1 Charité, Psychiatrische Universitätsklinik, Berlin, Germany, 2 Physikalisch Technische Bundesanstalt, Berlin, Germany) Introduction: (1) Processing of rewarding stimuli is associated with increased firing rate of dopamine neurons in the ventral striatum, a core region of the brain reward system. Psychiatric diseases with dysfunctional reward behavior, like schizophrenia, are associated with abnormal dopaminergic neurotransmission and dysfunctional activation of the ventral striatum (Juckel, 2006). (2) A close interaction between dopamine and glutamate has been proposed to play an important role in reward processing and in the pathophysiology of schizophrenia [Carlsson, 1990]. (3) In humans, aspects of dopamine function may be reflected by the BOLD activity of the ventral striatum during presentation of rewarding stimuli [Juckel, 2006, 1990], and glutamatergic function
Juckel G. Neuroimage 2006;29:409–16. Carlsson M. Trends Neurosci 1990;13:272–6. Knutson B. J Neurosci 2001;21:RC159. Schubert F. Neuroimage 2004;21:1762–71. Fox P. Nat Rev Neurosci 2002;3:319–21. Nielsen F. Neuroimage 2002;16. doi:10.1016/j.clinph.2008.07.059
61. Electrophysiological study in juvenile asymmetric segmental spinal muscular atrophy (Hirayama disease)—W. Dietrich 1, F. Erbguth 1, G. Berger 1, R. Gerlach 2, I. Bär 2, B. Schmid 1 (1 Klinikum Nürnberg, Klinik für Neurologie, Nürnberg, Germany, 2 Klinikum Nürnberg, Abteilung für Radiologie, Nürnberg, Germany) Hirayama disease (HD) is characterized by slowly progressive distal amyotrophy of upper limb, usually monolateral, occurring predominantly in young Asian men. The aetiology of HD is not well