Differentielle Effekte der tiefen Hirnstimulation von STN und VIM auf kognitive Komponenten der Wortproduktion

Einleitung: Die Behandlung von Morbus Parkinson und essentiellem Tremor durch die Tiefenhirnstimulation (THS) im basalganglionären Nucleus subthalamicus (STN) und thalamischen Nucleus ventralis intermedius (VIM) führt zur Verbesserung entsprechender Bewegungsstörungen. Obwohl THS bzgl. kognitiver Nebenwirkungen als relativ sicher gilt, wurden negative Auswirkungen auf Wortflüssigkeit berichtet. Grundlagen dessen sind unklar, da Wortflüssigkeitsleistungen exekutive und lexikalische Prozesse beinhalten, deren Bezüge zu THS-Zielstrukturen unbekannt sind. Daher wurde zur Differenzierung (i) kognitiver THS- Wirkungen und (ii) Funktionen von THS-Zielstrukturen der Einfluss von STN- vs. VIM- Stimulation auf unterschiedliche Aspekte der Wortproduktion bestimmt. Methodik: Zur Analyse der Wortproduktionsleistung (mittels Regensburger Wortflüssigkeitstest) wurde die „temporale Clusteranalyse“ verwendet, die eine formale Differenzierung schneller (Cluster) vs. langsamer (Switches) Wortproduktionsphasen erlaubt. Cluster gelten als Ergebnis automatischer Aktivitätsausbreitung assoziierter lexikalischer Informationen und reflektieren somit sprachbezogene Netzwerkprozesse. Switches gelten als aufmerksamkeitsabhängige Prozesse, die Transitionen zwischen lexikalischen Assoziationsfeldern widerspiegeln. Um zu überprüfen, ob sich bisher nur im semantischen Kontext erprobte temporale Clusteranalysen auch für Untersuchungen mit Standardwortflüssigkeitsaufgaben eignen, haben wir in Studie 1 das Cluster-/Switchverhalten von 42 gesunden Probanden in einer phonematischen VF-Aufgabe analysiert. In den Studien 2/3 wurde das Cluster-/Switchverhalten von 11/13 Patienten mit STN-THS/VIM-THS im aktiven (STIM-ON-) und inaktiven (STIM-OFF) Stimulationszustand untersucht. Die Ergebnisse wurden jeweils mit den Leistungen gesunder Kontrollprobanden verglichen. Ergebnisse: Studie 1 zeigte, dass im Cluster produzierte Wörter in rein phonematischen VF- Aufgaben semantisch und phonematisch stärker verwandt waren als Switch-bezogene Wörter. Höhere phonematische Wortassoziationswerte gingen einher mit vermehrter, höhere semantische Assoziationswerte mit geringerer Wortflüssigkeitsleistung. Bezüglich THS-Wirkungen in verschiedenen subkortikalen Strukturen ergaben sich unterschiedliche Stimulationswirkungen auf das Cluster-/Switchverhalten. Studie 2 zeigte, dass im STN STIM-ON mehr Switches mit geringeren Switchzeiten generiert wurden als im STIM- OFF, während Clusterparameter unbeeinflusst blieben. In Studie 3 wurde ein gegensätzliches Muster identifiziert: im VIM war STIM-ON mit langsameren Clusterzeiten verbunden als STIM- OFF, ohne Effekte auf die Switchparameter zu haben. Verglichen mit Kontrollprobanden generierten beide Patientengruppen unabhängig vom Stimulationszustand geringere VF- Leistungen. Diskussion: Studie 1 zeigt, dass die temporale Clusteranalyse sowohl im semantischen als auch im phonematischen Kontext exekutive und lexikalische Aspekte der VF-Leistung voneinander abgrenzt. Diese Ergebnisse erweitern Annahmen zum „Semantic Default“-Modus lexikalischer Produktion (siehe Hauptteil) und legitimieren die Verwendung von Standardwortflüssigkeitsaufgaben im gegebenen Kontext. Die Patientenstudien deuten darauf hin, dass der STN keine ‚lexikalische Bedeutung‘ hat, jedoch prozedurale Wortproduktionsprozesse unterstützt, passend zur Einbettung in fronto- striatäre Netzwerke mit vermuteten Exekutivfunktionen. VIM-THS scheint mit thalamischen Funktionen automatischer lexikalischer Informationsrekrutierung zu interferieren. Die Ergebnisse werden unter konzeptuellen und klinischen Gesichtspunkten diskutiert.Introduction: Treatment of Parkinson’s disease and essential tremor via deep brain stimulation (DBS) of the basal ganglia subthalamic nucleus (STN) and the thalamic ventral intermedius nucleus (VIM) improves respective motor deficits. Although DBS is relatively safe regarding cognitive side-effects, negative effects on verbal fluency (VF) have been reported. Reasons for this finding are unclear, since VF-performance includes executive and lexical processes with unknown relation to DBS target structures. For differentiating (i) cognitive DBS-effects and (ii) functions of DBS-structures, we studied effects of STN- vs. VIM-stimulation on different aspects of VF. Method: VF-performance (tested with the standard “Regensburger Wortflüssigkeitstest”) was analysed using the ‘temporal cluster analysis’, allowing a formal distinction between faster (clusters) vs. slower (switches) word production phases. Clusters are regarded as the result of automatic activation of associated word-related information throughout lexical networks, whereas switches rather mirror attention-demanding processes for the transition from a given lexical field to another. To find out whether temporal cluster analysis, which was previously used only in semantic contexts, can be reasonably applied in standard VF-tasks, we investigated cluster and switch performance of 42 healthy subjects in a phonemic VF-task in study 1. In studies 2/3 we analysed the cluster and switch performance of 11/13 patients with STN- DBS/VIM-DBS in the stimulated (STIM-ON) and non-stimulated (STIM-OFF) DBS-condition. Results were compared to those of healthy controls. Results: Study 1 showed that in a phonemic VF-task clustered words had higher semantic and phonemic relations than switch-related words. A stronger phonemic relatedness was associated with increased, a stronger semantic relatedness with decreased VF-performance. Regarding DBS-effects in distinct subcortical structures, different stimulation-effects on cluster and switch performance were found. Study 2 showed that in the STN STIM-ON more switches with slower switch times were generated than in STIM-OFF. Cluster parameters were not affected. Study 3 revealed a contrary pattern: in VIM, STIM-ON was accompanied by slower cluster times compared to STIM-OFF, without affecting switch parameters. Compared to control subjects both patient groups had decreased VF-performances, regardless of their stimulation condition. Discussion: Study 1 indicates that temporal cluster analysis can differentiate executive and lexical aspects of VF-performance in semantic and phonemic contexts. The results extend assumptions about a “semantic default” mode of lexical production (see main text) and legitimize the use of standard VF-tasks in the given framework. The patient studies suggest that the STN has no proper “lexical relevance”; however, it seems to support procedural VF-processes, compatible with its embedding in frontostriatal networks with suggested executive functions. VIM-DBS seems to interfere with thalamic functions of automatic lexical information recruitment. Results are discussed in conceptual and clinical contexts

Deep Brain Stimulation of the Subthalamic Nucleus Improves Lexical Switching in Parkinsons Disease Patients.

OBJECTIVE:Reduced verbal fluency (VF) has been reported in patients with Parkinson's disease (PD), especially those treated by Deep Brain Stimulation of the subthalamic nucleus (STN DBS). To delineate the nature of this dysfunction we aimed at identifying the particular VF-related operations modified by STN DBS. METHOD:Eleven PD patients performed VF tasks in their STN DBS ON and OFF condition. To differentiate VF-components modulated by the stimulation, a temporal cluster analysis was performed, separating production spurts (i.e., 'clusters' as correlates of automatic activation spread within lexical fields) from slower cluster transitions (i.e., 'switches' reflecting set-shifting towards new lexical fields). The results were compared to those of eleven healthy control subjects. RESULTS:PD patients produced significantly more switches accompanied by shorter switch times in the STN DBS ON compared to the STN DBS OFF condition. The number of clusters and time intervals between words within clusters were not affected by the treatment state. Although switch behavior in patients with DBS ON improved, their task performance was still lower compared to that of healthy controls. DISCUSSION:Beyond impacting on motor symptoms, STN DBS seems to influence the dynamics of cognitive procedures. Specifically, the results are in line with basal ganglia roles for cognitive switching, in the particular case of VF, from prevailing lexical concepts to new ones

The Absoluteness of Semantic Processing: Lessons from the Analysis of Temporal Clusters in Phonemic Verbal Fluency

<div><p>Background</p><p>For word production, we may consciously pursue semantic or phonological search strategies, but it is uncertain whether we can retrieve the different aspects of lexical information independently from each other. We therefore studied the spread of semantic information into words produced under exclusively phonemic task demands.</p><p>Methods</p><p>42 subjects participated in a letter verbal fluency task, demanding the production of as many <i>s</i>-words as possible in two minutes. Based on curve fittings for the time courses of word production, output spurts (temporal clusters) considered to reflect rapid lexical retrieval based on automatic activation spread, were identified. Semantic and phonemic word relatedness within versus between these clusters was assessed by respective scores (0 meaning no relation, 4 maximum relation).</p><p>Results</p><p>Subjects produced 27.5 (±9.4) words belonging to 6.7 (±2.4) clusters. Both phonemically and semantically words were more related within clusters than between clusters (phon: 0.33±0.22 vs. 0.19±0.17, <i>p</i><.01; sem: 0.65±0.29 vs. 0.37±0.29, <i>p</i><.01). Whereas the extent of phonemic relatedness correlated with high task performance, the contrary was the case for the extent of semantic relatedness.</p><p>Conclusion</p><p>The results indicate that semantic information spread occurs, even if the consciously pursued word search strategy is purely phonological. This, together with the negative correlation between semantic relatedness and verbal output suits the idea of a semantic default mode of lexical search, acting against rapid task performance in the given scenario of phonemic verbal fluency. The simultaneity of enhanced semantic and phonemic word relatedness within the same temporal cluster boundaries suggests an interaction between content and sound-related information whenever a new semantic field has been opened.</p></div

Cascaded lexical search model.

<p>Clusters are thought to reflect the cascaded processing of semantic and phonological information: In this view, word search originates from the activation of semantic fields (A, B, C). During respective field scans a parallel phonological search stream is activated. In letter VF, words would be released if a semantic concept can be aligned with a suitable phonological representation. A cluster transition occurs upon completion of these automatic and therefore rapid operations per field, when the next semantic category has to be accessed and phonemic alignment is restarted.</p

Cluster and switching results.

<p>Cluster and switching results.</p

Intact lexicon running slowly--prolonged response latencies in patients with subthalamic DBS and verbal fluency deficits.

BACKGROUND: Verbal Fluency is reduced in patients with Parkinson's disease, particularly if treated with deep brain stimulation. This deficit could arise from general factors, such as reduced working speed or from dysfunctions in specific lexical domains. OBJECTIVE: To test whether DBS-associated Verbal Fluency deficits are accompanied by changed dynamics of word processing. METHODS: 21 Parkinson's disease patients with and 26 without deep brain stimulation of the subthalamic nucleus as well as 19 healthy controls participated in the study. They engaged in Verbal Fluency and (primed) Lexical Decision Tasks, testing phonemic and semantic word production and processing time. Most patients performed the experiments twice, ON and OFF stimulation or, respectively, dopaminergic drugs. RESULTS: Patients generally produced abnormally few words in the Verbal Fluency Task. This deficit was more severe in patients with deep brain stimulation who additionally showed prolonged response latencies in the Lexical Decision Task. Slowing was independent of semantic and phonemic word priming. No significant changes of performance accuracy were obtained. The results were independent from the treatment ON or OFF conditions. CONCLUSION: Low word production in patients with deep brain stimulation was accompanied by prolonged latencies for lexical decisions. No indication was found that the latter slowing was due to specific lexical dysfunctions, so that it probably reflects a general reduction of cognitive working speed, also evident on the level of Verbal Fluency. The described abnormalities seem to reflect subtle sequelae of the surgical procedure for deep brain stimulation rather than of the proper neurostimulation

Relatedness scores between and within clusters.

<p>Relatedness scores between and within clusters.</p

STN DBS ON-OFF Comparison.

<p>Fig 2 shows the ON-OFF comparison of VF performance in the patient group. Values indicate the mean (± standard deviations) for the number of switches, the number of clusters, and the number of words. * significant treatment-related effect at a <i>p</i>-level < .05.</p

Baseline Characteristics.

<p>Baseline Characteristics.</p

Example of a curve fit.

<p>Scheme of best-fitting curve for an individual VF course; circled segments represent clusters with faster than predicted word production as opposed to switches between thus defined clusters.</p