Jerome J. Maller

A Meta-Analytic Study of Changes in Brain Activation in Depression

Objective: A large number of studies with considerably variable methods have been performed to investigate brain regions involved in the pathophysiology of major depressive disorder. The aim of this study was to use a quantitative meta‐analytic technique to synthesise the results of much of this research. Methods: Three separate quantitative meta‐analytical studies were conducted using the Activation Likelihood Estimation technique. Analysis was performed on three types of studies: (1) those conducted at rest comparing brain activation in patients with depression and controls; (2) those involving brain changes following antidepressant treatment; and (3) those comparing brain activation patterns induced by the induction of positive or negative emotion in patients with depression compared with controls. Results: There appears to be a complex series of areas of the brain implicated in the pathophysiology of depression although limited overlap was found across imaging paradigms. This included a network of regions including frontal and temporal cortex as well as the insula and cerebellum that are hypoactive in depressed subjects and in which there is increase in activity with treatment. There was a corresponding set of subcortical and limbic regions in which opposite changes were found. Conclusions: There is limited overlap between the brain regions identified using differing imaging methods. The most consistently identified regions include areas of the anterior cingulate, dorsolateral, medial and inferior prefrontal cortex, insula, superior temporal gyrus, basal ganglia and cerebellum. Further research is required to identify if different imaging methods are identifying complementary networks that are equally involved in the disorder. Hum Brain Mapp, 2008.

A Randomized Trial of rTMS Targeted with MRI Based Neuro-Navigation in Treatment-Resistant Depression

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subjects MRI scan. There was an overall significant reduction in the Montgomery–Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

Long-Interval Cortical Inhibition from the Dorsolateral Prefrontal Cortex : a TMS-EEG Study

Several studies have demonstrated that cortical inhibition (CI) can be recorded by paired transcranial magnetic stimulation (TMS) of the motor cortex and recorded by surface electromyography (EMG). However, recording CI from other cortical regions that are more closely associated with the pathophysiology of some neurological and psychiatric disorders (eg, dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously unattainable. This study, therefore, was designed to investigate whether CI could be measured directly from the motor cortex and DLPFC by combining TMS with electroencephalography (EEG). Long-interval CI (LICI) is a TMS paradigm that was used to index CI in the motor cortex and DLPFC in healthy subjects. In the motor cortex, LICI resulted in significant suppression (32.8±30.5%) of mean cortical evoked activity on EEG, which was strongly correlated with LICI recorded by EMG. In the DLPFC, LICI resulted in significant suppression (30.1±26.9%) of mean cortical evoked activity and also correlated with LICI in the motor cortex. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurological and psychiatric disorders.

Memory complaints in a community sample aged 60–64 years: associations with cognitive functioning, psychiatric symptoms, medical conditions, APOE genotype, hippocampus and amygdala volumes, and white-matter hyperintensities

BACKGROUND Previous research has found that depression is a major cause of memory complaints. However, there is evidence that memory complaints also weakly predict cognitive decline and dementia. The present study examined a range of possible determinants of memory complaints, covering psychiatric and personality factors, medical history, cognitive test performance, and biological risk factors for dementia (APOE genotype, hippocampus and amygdala volumes, and white-matter hyperintensities). METHOD A community survey was carried out with 2546 persons aged 60-64 years living in Canberra and Queanbeyan, Australia. Participants were asked about memory problems which interfered with daily life and whether medical help had been sought. A randomly selected subsample of 476 persons was given a brain MRI scan. RESULTS Participants with memory complaints were found to have poorer memory test performance, more depression and anxiety symptoms, have higher scores on personality traits involving negative affect, and to have worse physical health. Multivariate analyses showed that measures of cognitive performance did not make a unique contribution to the prediction of memory complaints above that of the other categories of predictors. Those with memory complaints did not differ on any of the biological risk factors for dementia. CONCLUSION In a community sample aged 60-64 years, memory complaints were most closely related to psychiatric symptoms, personality characteristics and poor physical health. There was no evidence of brain changes indicating early dementia.

Superior temporal gyrus volume change in schizophrenia: A review on Region of Interest volumetric studies ☆

Imaging studies of schizophrenia (SCZ) have repeatedly demonstrated volume differences in superior temporal gyrus (STG) and its subregions. Among them, some studies employed the Region of Interest (ROI) method. We carried out a systematic review of the published literature on STG volumetry MRI studies to examine the potential of ROI method for identifying specific structural differences and correlations with clinical variables including hallucinations and thought disorder symptoms in SCZ. Forty-six studies were identified as suitable for review and analysis including 1444 patients with SCZ and 1327 controls. Female and left-handed subjects are under-represented in the literature and insight from sex and handedness differences may be lost. Thirty-five studies reported significant differences in STG or subregional volumes including bilateral or unilateral ROI, and volume reduction was the most common change in SCZ. Thirty studies reported correlations between volume changes and clinical symptoms or syndromes and 18 found positive results. Among them, left STG or subregions appear to be more involved in the generation of hallucinations and thought disorder than right side. The majority of five follow-up studies found evidence of progressive changes in volumes. Clinical heterogeneity, MRI acquisition parameters, anatomical landmarks for ROI, and sample characteristics, are likely to be the main factors leading to heterogeneous results. Clearly this research links pathophysiological changes in the STG with the development of hallucinations and thought disorder in patients with SCZ, especially in the left side. There is a suggestion that these changes may be progressive but this requires more thorough and comprehensive assessment.

Optimal Transcranial Magnetic Stimulation Coil Placement for Targeting the Dorsolateral Prefrontal Cortex Using Novel Magnetic Resonance Image-Guided Neuronavigation

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including major depressive disorder and schizophrenia. In this regard, the DLPFC has been targeted in repetitive transcranial magnetic stimulation (rTMS) studies as a form of treatment to those patients who are resistant to medications. The ‘5‐cm method’ and the ‘10‐20 method’ for positioning the transcranial magnetic stimulation (TMS) coil over DLPFC have been scrutinised due to poor targeting accuracies attributed to inter‐subject variability. We evaluated the accuracy of such methods to localise the DLPFC on the scalp in 15 healthy subjects and compared them with our novel neuronavigational method, which first estimates the DLPFC position in the cortex based on a standard template and then determines the most appropriate position on the scalp in which to place the TMS coil. Our neuronavigational method yielded a scalp position for the left DLPFC between electrodes F3 and F5 in standard space and was closest to electrode F5 in individual space. Further, we found that there was significantly less inter‐subject variability using our neuronavigational method for localising the DLPFC on the scalp compared with the ‘5‐cm method’ and the ‘10‐20 method’. Our findings also suggest that the ‘10‐20 method’ is superior to the ‘5‐cm method’ in reducing inter‐subject variability and that electrode F5 should be the stimulation location of choice when MRI co‐registration is not available. Hum Brain Mapp, 2010.

Traumatic brain injury, major depression, and diffusion tensor imaging: Making connections ☆

UNLABELLED It is common for depression to develop after traumatic brain injury (TBI), yet despite poorer recovery, there is a lack in our understanding of whether post-TBI brain changes involved in depression are akin to those in people with depression without TBI. Modern neuroimaging has helped recognize degrees of diffuse axonal injury (DAI) as being related to extent of TBI, but its ability to predict long-term functioning is limited and has not been considered in the context of post-TBI depression. A more recent brain imaging technique (diffusion tensor imaging; DTI) can measure the integrity of white matter by measuring the directionality or anisotropy of water molecule diffusion along the axons of nerve fibers. AIM To review DTI results in the TBI and depression literatures to determine whether this can elucidate the etiology of the development of depression after TBI. METHOD We reviewed the TBI/DTI (40 articles) and depression/DTI literatures (17 articles). No articles were found that used DTI to investigate depression post-TBI, although there were some common brain regions identified between the TBI/DTI and depression/DTI studies, including frontotemporal, corpus callosum, and structures contained within the basal ganglia. Specifically, the internal capsule was commonly reported to have significantly reduced fractional anisotropy, which agrees with deep brain stimulation studies. CONCLUSION It is suggested that measuring the degree of DAI by utilizing DTI in those with or without depression post-TBI, will greatly enhance prediction of functional outcome.

Corpus callosum size, reaction time speed and variability in mild cognitive disorders and in a normative sample

Intra-individual variability in reaction time increases with age and with neurological disorders, but the neural correlates of this increased variability remain uncertain. We hypothesized that both faster mean reaction time (RT) and less intra-individual RT variability would be associated with larger corpus callosum (CC) size in older adults, and that these associations would be stronger in adults with mild cognitive disorders. A normative sample (n=432) and a sample with mild cognitive disorders (n=57) were compared on CC area, RT mean and RT variability adjusting for age, sex, education, APOE genotype, smoking, alcohol consumption, grip strength, visual acuity, handedness and lung function. Samples did not differ in CC area or intra-cranial volume. In the normative sample, simple RT (SRT) and choice RT (CRT) were negatively associated with CC area but there were minimal associations between CC area and intra-individual RT variability. In the mild cognitive disorders sample, SRT, CRT and intra-individual variability on the SRT task were associated with CC area. Increased RT variability explained up to 12.7 percent of the variance in CC area in the sample with mild cognitive disorders, but less than 1 percent of the variance in CC area in the normative sample. There were no associations with APOE genotype. We conclude that intra-individual variability is associated with CC area in mild cognitive disorders, but not in normal aging. We propose that biological limits on reserve capacity must occur in mild cognitive disorders that result in stronger brain-behavior relationships being observed.

The Brain Reserve Hypothesis, Brain Atrophy and Aging

Background: Researchers have used the concept of brain reserve to explain the dissociation between pathological brain damage and cognitive and functional performance. A variety of brain reserve hypotheses exist, and different empirical strategies have been employed to investigate these variants. Objective: The study investigates (i) the relationship between measures of brain burden (atrophy, white matter hyperintensities (WMH)) and measures of reserve (education, creativity, and intelligence); (ii) the relationship between cognitive decline and reserve; (iii) whether measures of reserve mediate the effect of atrophy on estimated cognitive change, and (iv) the association between brain risk factors, education and atrophy. Methods: A cross-sectional study of a sample of 446 individuals 60–64 years of age who underwent MRI scans as part of a large epidemiological study. Measures were taken of education, intelligence, creativity, cognitive speed, brain volume, WMH, estimated cognitive decline from earlier in life and brain atrophy. Results: No association was found between estimated cognitive decline and brain burden (atrophy, WMH). Risk factors for brain insult were not associated with greater brain atrophy in the less well educated. Neither education, nor any other measure including intelligence or creativity, provided a buffer for cognitive decline in individuals with high levels of brain atrophy. Conclusion: Little support was found for the brain reserve hypothesis.

GABA and cortical inhibition in motor and non-motor regions using combined TMS-EEG: A time analysis

OBJECTIVE The induction of long interval cortical inhibition (LICI) in motor cortex with paired pulse transcranial magnetic stimulation (ppTMS) is an established paradigm for the assessment of cortical inhibition, proposed to be related to GABA(B) receptor inhibitory neurotransmission. This study aimed to further evaluate recent methods of the assessment of LICI in non motor regions with ppTMS and electroencephalography (EEG). METHODS ppTMS was applied using a single coil to the motor and dorsolateral prefrontal cortex (DLPFC) in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. RESULTS In the motor cortex, LICI resulted in significant suppression in mean cortical evoked activity on EEG between 75 and 250 ms following delivery of the test stimulus. Maximal inhibition was seen from 50 to 250 ms in DLPFC, and between 50 and 175 ms in the parietal lobe. CONCLUSIONS ppTMS may be used to produce LICI in several cortical regions with a time course similar to known GABA(B) activity. SIGNIFICANCE ppTMS induction of LICI can be recorded by combining TMS with EEG and seems to relate to GABA(B) activity.