Arthur Wunderlich

Brain activation during human navigation: gender-different neural networks as substrate of performance

Visuospatial navigation in animals and human subjects is generally studied using maze exploration. We used functional MRI to observe brain activation in male and female subjects as they searched for the way out of a complex, three-dimensional, virtual-reality maze. Navigation activated the medial occipital gyri, lateral and medial parietal regions, posterior cingulate and parahippocampal gyri as well as the right hippocampus proper. Gender-specific group analysis revealed distinct activation of the left hippocampus in males, whereas females consistently recruited right parietal and right prefrontal cortex. Thus we demonstrate a neural substrate of well established human gender differences in spatial-cognition performance.

Emotional context modulates subsequent memory effect

Emotions have been shown to modulate memory processes. However, the neuronal substrate underlying these modulatory effects is largely unknown. Using event-related functional magnetic resonance imaging (fMRI), we investigated whether the context of emotional encoding modulates brain activation predictive for subsequent recall of emotionally neutral material. While inferior frontal activation predicted recall in general, our data show that in a positive encoding context, recall was predicted by activation of right anterior parahippocampal and extrastriate visual brain areas, whereas in a negative encoding context, recall was predicted by activation of the amygdala. Thus, we could demonstrate that successful episodic encoding is differentially modulated by emotional context. These results contribute to the understanding of the interaction of emotion and cognition and moreover are of general relevance for studies of episodic memory.

The navigation of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a new method for investigating cortical information processing and for investigating therapeutic applications in psychiatry and neurology. A common problem of most studies in this field regards the localization of the magnetic coil with respect to the cortex. This article reviews the currently used methods and proposes a neuronavigational approach. The method of neuronavigated TMS is described and discussed in detail. It is used to guide the magnetic coil on an individual basis to a structurally or functionally predetermined cortical area while monitoring the location of the coil in relation to the subjects head in real time. Possible applications of TMS in combination with functional neuroimaging in clinical research within a cognitive neuroscience framework are discussed. Future applications of TMS should take individual anatomy into account, and neuronavigation provides the means to do so.

Subjective memory complaints: Objective neural markers in patients with Alzheimer's disease and major depressive disorder

Patients with probable Alzheimers disease and depressive patients frequently present with subjective memory complaints. Objective distinction of underlying neuronal substrate malfunction and early cross‐sectional differential diagnosis have been elusive thus far. We used repetitive learning and free recall of abstract geometric patterns during functional magnetic resonance imaging to assess episodic memory in older subjects (ages 56–64 years) who sought first‐time medical attention with subjective memory complaints and were diagnosed with probable Alzheimers disease (NINCDS‐ADRDA criteria; ages 51–67 years) or major depressive disorder (DSM‐IV; ages 50–65 years). Contrasting healthy seniors or depressive patients with Alzheimers disease patients revealed superiority of hippocampal activation. Contrasting Alzheimers disease patients with seniors showed bilateral prefrontal activity as a correlate of futile compensation of episodic memory failure. Contrasting patients who had major depressive disorder with seniors or patients who had Alzheimers disease showed bilateral activation of the orbitofrontal cortex and the anterior cingulate. Subjective memory complaints may be classified objectively and very early with functional magnetic resonance imaging of episodic memory in groups of patients with Alzheimers disease and depressive syndrome. This may facilitate drug trials with evaluation of specific treatments, but further studies will be needed to establish the differential diagnosis for the individual patient.

The neural correlates of driving.

We studied 12 healthy subjects with fMRI while they performed a driving simulation task. In the active condition they steered the car themselves (driving), in the passive condition a person from outside the scanner was steering the car (passive driving). Common activations in both conditions were found in occipital and parietal regions bilaterally. Activity specifically associated with driving was found only in the sensorimotor cortex and the cerebellum. Compared to passive driving, activity during driving was reduced in numerous brain regions including MT/MST. It is concluded that simulated driving requires mainly perceptual–motor integration and that the limited cognitive capacity model of driving has to be revised.

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis.

Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimers disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.

No hypofrontality, but absence of prefrontal lateralization comparing verbal and spatial working memory in schizophrenia

Hypofrontality and decreased lateralization have been two major, albeit controversial, results from functional neuroimaging studies of schizophrenia. We used fMRI to study cortical activation during a verbal and spatial working memory (WM) task (2-back) in 15 inpatients acutely ill with schizophrenia and 15 matched control subjects. We hypothesized (i) hypofrontality in patients in both tasks and (ii) decreased lateralization of prefrontal activation in patients under the assumption that, in controls, left prefrontal cortex (PFC) is engaged preferentially in the verbal task (verbal domain dominance) and the right prefrontal cortex is engaged preferentially in the spatial task (spatial domain dominance). Our results showed no significant differences in frontal activation between controls and patients, i.e. no hypofrontality in patients, even at a very liberal threshold (p<0.01). This may be explained by the fact that nearly all patients studied received atypical neuroleptics. Nonetheless, we found evidence for more subtle, domain-related prefrontal dysfunction. Whereas controls showed verbal WM domain dominance in left inferior frontal cortex and spatial WM domain dominance in right prefrontal cortex, these domain dominance effects were absent in the patient group, i.e. there were no lateralization effects. Finally, only patients showed an inverse correlation between performance and right prefrontal activation in verbal WM. We conclude that the finding of hypofrontality may depend on the medication of the patients and that there is prefrontal dysfunction even in the absence of hypofrontality.

Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex.

Neuroimaging studies in humans have shown that different working memory (WM) tasks recruit a common bilateral fronto-parietal cortical network. Animal studies as well as neuroimaging studies in humans have suggested that this network, in particular the prefrontal cortex, is preferentially recruited when material from different domains (e.g. spatial information or verbal/object information) has to be memorized. Early imaging studies have suggested qualitative dissociations in the prefrontal cortex for spatial and object/verbal WM, either in a left-right or a ventral-dorsal dimension. However, results from different studies are inconsistent. Moreover, recent fMRI studies have failed to find evidence for domain dependent dissociations of WM-related activity in prefrontal cortex. Here we present evidence from two independent fMRI studies using physically identical stimuli in a verbal and spatial WM task showing that domain dominance for WM does indeed exist, although only in the form of quantitative differences in activation and not in the form of a dissociation with different prefrontal regions showing mutually exclusive activation in different domains. Our results support a mixed dimension model of domain dominance for WM within the prefrontal cortex, with left ventral prefrontal cortex (PFC) supporting preferentially verbal WM and right dorsal PFC supporting preferentially spatial WM. The concept of domain dominance is discussed in the light of recent theories of prefrontal cortex function.

Spatial congruence of neuronavigated transcranial magnetic stimulation and functional neuroimaging.

OBJECTIVES Transcranial magnetic stimulation (TMS) is progressively gaining relevance as a tool in cognitive neuroscience and clinical research. However, most studies in this field do not consider individual anatomy. Neuronavigational devices allow to guide the coil to a specific cortical area, predetermined by functional magnetic resonance imaging (fMRI). Therefore, it is crucial to know whether the area of a certain function as identified by fMRI corresponds to the area where the TMS should be placed in order to influence this function. METHODS We investigated the spatial relation between the cortical area activated by a motor task in fMRI and the area of magnetically evoked motor potentials (MEP) in 8 subjects, using a spacing of 5x5 mm. A neuronavigational system was adapted for coil positioning and for the registration of the stimulation coordinates. RESULTS A spatial divergence of the centers of gravity from fMRI and MEP was found with a mean distance of about 10 mm, with the MEP centers being, by a mean derivation of 7.5 mm, consistently anterior to the center of fMRI activation. However, regarding MEP areas and fMRI activities, a large overlap was found for stimulation intensities of both 110 and 120% motor threshold. CONCLUSIONS The combination of fMRI and neuronavigated TMS is useful for non-invasive investigation of individual cortical functions predetermined by fMRI. Whereas both are spatially by and large congruent, discrepencies in the exact spatial relation between MEP and fMRI areas should be considered and further studied.

fMRI for preoperative neurosurgical mapping of motor cortex and language in a clinical setting.

Purpose Identification of the precentral gyrus can be difficult in patients with brain tumors. The purpose of the current study was to evaluate the clinical usefulness of functional MRI (fMRI) in identifying motor cortex and speech areas as a part of preoperative neurosurgical planning. Method fMRI was performed using a 1.5 T MR unit in 41 patients with brain tumors. The motor paradigm was finger tapping and foot movement, whereas the language paradigm consisted of a two word semantic test. Statistical analysis of the data was done using the Kolmogorow-Smirnow test. Plots of signal intensities over time were created. Results The precentral gyrus was identified in 38 of 41 patients. In two patients, fMRI was not of acceptable quality due to motion artifacts. Speech areas were localized in 33 patients. In a typical clinical setting, the value of the method was graded “high.” Conclusion fMRI`s efficacy in the preoperative localization of language and motor areas is high. The method should become a routine adjunct for preoperative evaluation of brain tumors in the near future.