Kristina Hennig-Fast

Theta Burst Stimulation of the Prefrontal Cortex: Safety and Impact on Cognition, Mood, and Resting Electroencephalogram

BACKGROUND Because standard repetitive transcranial magnetic stimulation (rTMS) protocols exhibit post-stimulus effects of short duration, novel protocols such as theta burst stimulation (TBS), are promising approaches to enhance the effectiveness of rTMS. However, little is known about the side effect profile of such protocols. Thus, the present study explores whether TBS is safe particularly in terms of effects on cognition, mood, and electroencephalogram (EEG) measures in healthy subjects. METHODS Twenty-four healthy volunteers participated in 2 randomized, placebo-controlled, cross-over experiments and underwent continuous TBS (cTBS), intermittent TBS (iTBS), and shamTBS either over the left dorsolateral prefrontal cortex (DLPFC, n = 12) or the medial prefrontal cortices (mPFC, n = 12). Clinical side effects, performance in a neuropsychological battery, mood changes, and resting EEG were recorded. RESULTS Neither a seizure nor epileptiform EEG activity was observed. The most prominent side effect was the occurrence of vagal reactions during TBS; otherwise no serious side effects were found. Standardized low-resolution brain electromagnetic tomography showed current density changes in the alpha2 band after iTBS of the DLPFC, which remained detectable up to 50 min after stimulation. The few changes in neuropsychological performance were concordant with stimulation site. No impact on mood was detected. CONCLUSIONS Although TBS protocols of the human prefrontal cortex seem to be safe in healthy subjects, future studies need to address the occurrence of vagal reactions. Excitatory and inhibitory properties of motor cortex TBS might not be transferable to prefrontal sites, and the action of specific TBS protocols needs to be further investigated prior to clinical application.

Cognitive functioning in euthymic bipolar I and bipolar II patients

OBJECTIVE There is growing evidence of cognitive impairment as a trait factor in bipolar disorder. The generalizability of this finding is limited because previous studies have either focussed exclusively on bipolar I disorder or have analysed mixed patient groups. Thus, it is still largely unknown whether bipolar II patients perform differently from bipolar I patients on measures of cognitive functioning. METHODOLOGY A total of 65 patients with bipolar I disorder, 38 with bipolar II disorder, and 62 healthy controls participated in the study. Patients had to be euthymic for at least one month. Clinical and demographic variables were collected in a clinical interview and with the Structured Clinical Interview for DSM-IV. Cognitive functioning was assessed using a neuropsychological battery. Univariate and multivariate analyses of variance were conducted for analyzing possible differences between the groups. RESULTS The multivariate analysis of covariance (MANCOVA) indicated overall differences in neuropsychological performance between the three groups (Pillai Spur: F 1.96, p = 0.003). Post hoc comparisons revealed that patients with bipolar I disorder showed significantly lower scores in psychomotor speed, working memory, verbal learning, delayed memory, and executive functions than healthy controls. Patients with bipolar II disorder showed significant deficits in psychomotor speed, working memory, visual/constructional abilities, and executive functions compared to controls, but not on verbal learning and delayed memory. The two patient groups did not differ significantly from each other on any domain tested. CONCLUSION These results support a similar pattern of cognitive deficits in both subtypes of bipolar disorder.

Convergent Findings of Altered Functional and Structural Brain Connectivity in Individuals with High Functioning Autism: A Multimodal MRI Study

Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.

Cognitive functioning during methadone and buprenorphine treatment: Results of a randomized clinical trial.

Cognitive impairment in drug-dependent patients receiving methadone (MMP) maintenance treatment has been reported previously. We assessed cognitive functioning after at least 14 days of stable substitution treatment with buprenorphine (BUP) or MMP and after 8 to 10 weeks. We performed a randomized, nonblinded clinical trial in 59 drug-dependent patients receiving either BUP or MMP maintenance treatment and healthy normal controls (n = 24) matched for sex, age, and educational level. Thirteen patients dropped out of the study before the second testing was performed (BUP, n = 22; MMP, n = 24). A neuropsychological test battery was used to measure selective attention, verbal memory, motor/cognitive speed, and cognitive flexibility. In addition, subjective perceived stress was assessed with a questionnaire. Patients in both treatment groups performed equally well in all of the cognitive domains tested. Both BUP and MMP patients showed significantly improved concentration and executive functions after 8 to 10 weeks of stable substitution treatment. The control group achieved better results than the BUP and MMP groups in most cognitive domains, indicating cognitive impairment in the patients. Perceived stress did not show any significant change after 8 to 10 weeks of treatment, and no major differences were detected between the 3 groups. No effects of perceived stress on cognitive function were found. Our results indicate a cognitive impairment in patients receiving maintenance treatment with BUP or MMP compared with healthy controls. Selective attention improved in both patient groups during treatment. We propose that the improvement of attention may facilitate rehabilitation of drug-dependent patients.

A case of persistent retrograde amnesia following a dissociative fugue: Neuropsychological and neurofunctional underpinnings of loss of autobiographical memory and self-awareness

Autobiographical memory relies on complex interactions between episodic memory contents, associated emotions and a sense of self-continuity over the course of ones life. This paper reports a study based upon the case of the patient NN who suffered from a complete loss of autobiographical memory and awareness of identity subsequent to a dissociative fugue. Neuropsychological, behavioral, and functional neuroimaging tests converged on the conclusion that NN suffered from a selective retrograde amnesia following an episode of dissociative fugue, during which he had lost explicit knowledge and vivid memory of his personal past. NNs loss of self-related memories was mirrored in neurobiological changes after the fugue whereas his semantic memory remained intact. Although NN still claimed to suffer from a stable loss of autobiographical, self-relevant memories 1 year after the fugue state, a proportionate improvement in underlying fronto-temporal neuronal networks was evident at this point in time. In spite of this improvement in neuronal activation, his anterograde visual memory had been decreased. It is posited that our data provide evidence for the important role of visual processing in autobiographical memory as well as for the efficiency of protective control mechanisms that constitute functional retrograde amnesia.

Functional MRI study of memory-related brain regions in patients with depressive disorder.

BACKGROUND Structural imaging studies of patients suffering from depressive disorder have revealed reduced hippocampal volume in the majority of cases. The present study aimed specifically at investigating the hippocampal function in unipolar depression using functional magnetic resonance imaging (fMRI). METHODS Eleven unipolar depressed patients and eleven healthy control participants matched for age, gender and years of education underwent an associative learning paradigm during fMRI scanning. In the encoding condition of the paradigm, participants had to learn face-profession pairs. These pairs had to be remembered in the retrieval condition. RESULTS Hippocampal activity did not differ between depressive patients and control participants during encoding or retrieval. However, during encoding, depressive patients showed increased activity in the left parahippocampal gyrus and decreased activity in frontal and parietal regions. Retrieval of the associative pairs also yielded decreased activation patterns in depressive patients in frontal and parietal areas. LIMITATIONS The present findings may be limited by the small sample size of participants. Additionally the comparatively young age of the depressive sample could indicate a comparatively shorter duration of illness, and thereby less salient measurable hippocampal abnormalities. CONCLUSION The current study suggests that depression is associated with modified memory-related brain function. In particular the parahippocampal gyrus, the prefrontal cortex and parietal regions show functional alterations during associative learning. These structures as well as their interrelationships may play an important role in the pathogenesis of depressive disorder.

Neural correlates (ERP/fMRI) of voluntary selection in adult ADHD patients

Deficits in executive functions, e.g. voluntary selection, are considered central to the attention-deficit/hyperactivity disorder (ADHD). The aim of this simultaneous EEG/fMRI study was to examine associated neural correlates in ADHD patients. Patients with ADHD and healthy subjects performed an adapted go/nogo task including a voluntary selection condition allowing participants to freely decide, whether to press the response button. Electrophysiologically, response inhibition and voluntary selection led to fronto-central responses. The fMRI data revealed increased medial/lateral frontal and parietal activity during the voluntary selection task. Frontal brain responses were reduced in ADHD patients compared to controls during free responses, whereas parietal brain functions seemed to be unaffected. These results may indicate that selection processes are related to dysfunctions, predominantly in frontal brain regions in ADHD patients.

Subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia

From the clinical practice and some experimental studies, it is apparent that paranoid schizophrenia patients tend to assign emotional salience to neutral social stimuli. This aberrant cognitive bias has been conceptualized to result from increased emotional arousal, but direct empirical data are scarce. The aim of the present study was to quantify the subjective emotional arousal (SEA) evoked by emotionally non-salient (neutral) compared to emotionally salient (negative) social stimuli in schizophrenia patients and healthy controls. Thirty male inpatients with paranoid schizophrenia psychosis and 30 demographically matched healthy controls rated their level of SEA in response to neutral and negative social scenes from the International Affective Picture System and the Munich Affective Picture System. Schizophrenia patients compared to healthy controls had an increased overall SEA level. This relatively higher SEA was evoked only by the neutral but not by the negative social scenes. To our knowledge, the present study is the first designed to directly demonstrate subjective emotional over-arousal to neutral social scenes in paranoid schizophrenia. This finding might explain previous clinical and experimental data and could be viewed as the missing link between the primary neurobiological and secondary psychological mechanisms of paranoid psychotic-symptom formation. Furthermore, despite being very short and easy to perform, the task we used appeared to be sensitive enough to reveal emotional dysregulation, in terms of emotional disinhibition/hyperactivation in paranoid schizophrenia patients. Thus, it could have further research and clinical applications, including as a neurobehavioral probe for imaging studies.

After facing traumatic stress: Brain activation, cognition and stress coping in policemen

INTRODUCTION Resilience can be defined as the capacity to recover following stress or trauma exposure by adopting healthy strategies for dealing with trauma and stress. Although the importance of stress resilience has been recognized, the underlying neurocognitive mediators have not yet been identified. Thus, the primary goal of this study was to investigate memory-related brain activity in traumatized policemen who attended a pre-traumatic general stress coping program. METHOD Ten traumatized male police officers were compared to demographically matched non-traumatized officers (n=15) on associative memory by using a block design paradigm. Participants with either another psychiatric comorbidity or neurological disorder were excluded. During functional brain imaging (1.5-Tesla), face-profession pairs had to be encoded twice. For subsequent retrieval the faces were presented as cue stimuli for associating the category of the prior learned profession. Additionally, clinical pattern, stress coping style, and cognitive parameters were assessed. RESULTS Less BOLD activation was found in the hippocampus, parahippocampal gyrus and fusiform gyrus in the trauma group when compared with the non-trauma group during encoding. This was accompanied by slower reaction times in the trauma group during retrieval. Further impairments were found in context memory and in the use of positive cognitive coping strategies. DISCUSSION Support was provided for the presence of memory-related disturbances in brain activity associated with trauma even in a resilient population. The contribution of the changes in stress coping ability needs to be further examined in longitudinal studies.

Neuropsychological characteristics of highly dissociative healthy individuals.

ABSTRACT Objective: Dissociative disorders are characterized by disturbances in several neuropsychological domains, especially attention, memory, and consciousness. As a tendency to dissociate can also be observed in healthy individuals, and may be a risk factor for the development of dissociative disorders and posttraumatic stress disorder (PTSD), we were interested in the neuropsychological characteristics of these participants. Method: We examined attention, memory, and executive control functions in 17 high and 17 low dissociators without any psychiatric or neurological disorder and without prior experiences of trauma. Results: High dissociators showed relative performance deficiencies in tasks of memory for associative, context-dependent verbal material, visuospatial working memory, and executive control functions in terms of a heightened perseveration tendency and false positive errors. Conclusion: These cognitive deficits are consistent with models of dissociative disorders and dissociation in PTSD assuming a hippocampal and prefrontal dysfunction as a core factor. Mild cognitive impairments in otherwise healthy high dissociators may constitute a risk factor for the development of later PTSD or dissociative disorders.