Exploring the Relationship of Transdiagnostic Mood and Psychosis Symptom Domains with Motor Dysfunction.

BACKGROUND: A number of motor abnormalities have been reported in psychotic disorders, including dyskinesia and psychomotor slowing. There is also evidence for many of the same motor abnormalities in biological first-degree relatives and accruing evidence for motor abnormalities in bipolar disorder. In addition to motor dysfunction, there are also shared symptom domains amongst these populations. OBJECTIVES: We explored the associations of (1) current and lifetime psychosis and mood symptom domains and (2) domains of psychosis proneness with various domains of motor function in a transdiagnostic sample (n = 149). METHOD: Individuals with schizophrenia, schizoaffective disorder, or bipolar disorder, biological first-degree relatives of individuals with a psychotic disorder, and controls completed measures of psychomotor speed and movement fluidity, and neural activity related to motor preparation (stimulus-locked lateralized readiness potential, S-LRP) and execution (response-locked LRP) was assessed using EEG. All participants completed the Brief Psychiatric Rating Scale; patients were additionally assessed for lifetime psychosis and mood episode symptoms, and relatives and controls completed the Chapman psychosis proneness scales. RESULTS: Multiple regression revealed levels of current negative symptoms and mania were significantly positively associated with psychomotor slowing even after accounting for current antipsychotic medication dosage and duration of illness. S-LRP onset latency was significantly positively associated with magical ideation. CONCLUSION: Domains of motor function are associated with various mood and psychosis symptom domains in a transdiagnostic sample, which may provide insight into brain abnormalities relevant to the expression of symptoms across disorders.

A quantitative measure of handwriting dysfluency for assessing tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder commonly associated with chronic exposure to antidopaminergic medications, which may be in some cases disfiguring and socially disabling. The consensus from a growing body of research on the incidence and prevalence of TD in the modern era of antipsychotics indicates that this disorder has not disappeared continues to challenge the effective management of psychotic symptoms in patients with schizophrenia. A fundamental component in an effective strategy for managing TD is its reliable and accurate assessment. In the present study, we examined the clinical utility of a brief handwriting dysfluency measure for quantifying TD. Digitized samples of handwritten circles and loops were obtained from 62 psychosis patients with or without TD and from 50 healthy subjects. Two measures of dysfluent pen movements were extracted from each vertical pen stroke, including normalized jerk and the number of acceleration peaks. Tardive dyskinesia patients exhibited significantly higher dysfluency scores than non-TD patients and controls. Severity of handwriting movement dysfluency was correlated with Abnormal Involuntary Movement Scale severity ratings for some tasks. The procedure yielded high degrees of test-retest reliability. These results suggest that measures of handwriting movement dysfluency may be particularly useful for objectively evaluating the efficacy of pharmacotherapeutic strategies for treating TD.

Elucidating the relationships between two automated handwriting feature quantification systems for multiple pairwise comparisons.

Recent advances in complex automated handwriting identification systems have led to a lack of understandability of these systems' computational processes and features by the forensic handwriting examiners that they are designed to support. To mitigate this issue, this research studied the relationship between two systems: FLASH ID® , an automated handwriting/black box system that uses measurements extracted from a static image of handwriting, and MovAlyzeR® , a system that captures kinematic features from pen strokes. For this study, 33 writers each wrote 60 phrases from the London Letter using cursive writing and handprinting, which led to thousands of sample pairs for analysis. The dissimilarities between pairs of samples were calculated using two score functions (one for each system). The observed results indicate that dissimilarity scores based on kinematic spatial-geometric pen stroke features (e.g., amplitude and slant) have a statistically significant relationship with dissimilarity scores obtained using static, graph-based features used by the FLASH ID® system. Similar relationships were observed for temporal features (e.g., duration and velocity) but not pen pressure, and for both handprinting and cursive samples. These results strongly imply that both the current implementation of FLASH ID® and MovAlyzeR® rely on similar features sets when measuring differences in pairs of handwritten samples. These results suggest that studies of biometric discrimination using MovAlyzeR® , specifically those based on the spatial-geometric feature set, support the validity of biometric matching algorithms based on FLASH ID® output.

Voxel-based morphometry of patients with schizophrenia or bipolar I disorder: a matched control study.

Controlled trials provide critical tests of hypotheses generated by meta-analyses. Two recent meta-analyses have reported that gray matter volumes of schizophrenia and bipolar I patients differ in the amygdala, hippocampus, or perigenual anterior cingulate. The present magnetic resonance imaging study tested these hypotheses in a cross-sectional voxel-based morphometry (VBM) design of 17 chronic schizophrenia and 15 chronic bipolar patients and 21 healthy subjects matched for age, gender and duration of illness. Whole brain gray matter volume of both the schizophrenia and bipolar groups was smaller than among healthy control subjects. Regional voxel-wise comparisons showed that gray matter volume was smallest within frontal and temporal regions of both patient groups. Region of interest analyses found moderately large to large differences between schizophrenia and healthy subjects in the amygdala and hippocampus. There were no group differences in the perigenual anterior cingulate. When schizophrenia and bipolar groups were directly compared, the schizophrenia group showed smaller gray matter volumes in right subcortical regions involving the right hippocampus, putamen, and amygdala. The hippocampal and amygdala findings confirm predictions derived from recent meta-analyses. These structural abnormalities may be important factors in the differential manifestations of these two functional psychotic disorders.

Advances toward validating examiner writership opinion based on handwriting kinematics.

A National Research Council report on strengthening forensic science raised concern over the lack of scientific studies supporting the validity of examining and interpreting forensic evidence. However, establishing the foundational validity of subjective methods can be challenging. The present study aimed to establish the scientific validity of expert writership opinions and the two-stage approach to evidence interpretation using measures derived from research on handwriting motor control. Regression-based procedures were used to address two experimental questions: 1) what are the relative contributions of kinematic and pressure features in predicting examiner support for alternate writership propositions when examining pairs of questioned handwriting samples; and 2) to what extent does information about the rarity of the kinematic feature dissimilarity scores improve the accuracy of a predictive model based on dissimilarity alone. Regarding the first question, we identified a multifactor model consisting of feature dissimilarity scores and their population distributions having correlation coefficients (R2) of 0.84 and 0.88 for the same-writer and different-writers propositions, respectively. Temporal features contributed up to 21% to the predictive value of the model, whereas spatial features contributed only 9% and pen pressure contributed up to 17%. When we compared models reflecting a single-stage process (based on feature dissimilarities) of forming opinions with models reflecting a two-stage process (based on feature dissimilarities and rarity) we found that the two-stage models had an average of 15.25% greater predictive value than single-stage models. These findings support the scientific validity of FDE writership determinations and underscore the importance of the two-stage approach for evidence interpretation.

Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics.

Ongoing monitoring of neuroleptic-induced extrapyramidal side effects (EPS) is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Traditional approaches for assessing EPS such as Parkinsonism, tardive akathisia, or dyskinesia rely upon clinical ratings. However, these observer-based EPS severity ratings can be unreliable and are subject to examiner bias. In contrast, quantitative instrumental methods are less subject to bias. Most instrumental methods have only limited clinical utility because of their complexity and costs. This paper describes an easy-to-use instrumental approach based on handwriting movements for quantifying EPS. Here, we present findings from psychiatric patients treated with atypical (second generation) antipsychotics. The handwriting task consisted of a sentence written several times within a 2 cm vertical boundary at a comfortable speed using an inkless pen and digitizing tablet. Kinematic variables including movement duration, peak vertical velocity and the number of acceleration peaks, and average normalized jerk (a measure of smoothness) for each up or down stroke and their submovements were analyzed. Results from 59 psychosis patients and 46 healthy comparison subjects revealed significant slowing and dysfluency in patients compared to controls. We observed differences across medications and daily dose. These findings support the ecological validity of handwriting movement analysis as an objective behavioral biomarker for quantifying the effects of antipsychotic medication and dose on the motor system.

Use of an Automated System to Evaluate Feature Dissimilarities in Handwriting Under a Two-Stage Evaluative Process*, †.

The two-stage evaluative process is an established framework utilized by forensic document examiners (FDEs) for reaching a conclusion about the source(s) of handwritten evidence. In the second, or discrimination, stage, the examiner attempts to estimate the rarity of observations in a relevant background population. Unfortunately, control samples from a relevant background population are often unavailable, leaving the FDE to reach this determination based on subjective experience. Automated handwriting feature recognition systems are capable of performing both feature comparison and discrimination, yet these systems have not been subjected to empirical validation studies. In the present study, we repurposed a commercially available automated system to generate empirical distributions for ranking feature dissimilarity scores among pairs of handwritten phrases. The blinded results of this automated process were used to survey an international cohort of 36 FDEs regarding their strength of support for same- and different-writer propositions. The survey served to cross-validate FDE decision-making under the two-stage approach. Results from the survey demonstrated a clear pattern of response consistent with ground truth. Predictive regression analyses indicated that the automated feature dissimilarity scores and the log of their cumulative distribution functions accounted for 72% of the variability in FDE opinions. This study demonstrated that feature dissimilarity scores acquired using automated processes and their distributions are closely aligned with FDE decision-making processes supporting the heuristic value of the two-stage evaluative framework.

Signature dynamics in Alzheimer's disease.

Forensic document examiners are often called upon to opine on the authenticity of handwritten signatures by individuals with diminished mental capacity. Legal arguments surrounding the decisional capacity of an individual with dementia can be found in many cases involving wills, deeds, trusts, and contracts. The purpose of this study was to provide estimates of feature variability derived from dynamic analyses of signatures written by individuals with dementia of the Alzheimer type (AD) compared with age-comparable healthy individuals. Dynamic features of digitally captured signatures were analyzed to test the hypothesis that AD signature features will show greater variability compared with signatures from age-comparable healthy subjects. The study enrolled 69 AD and 74 age comparable healthy subjects. Results revealed four main findings from AD signatures: (1) that the temporal, spatial and fluency characteristics of signature formation did not differ from signatures of healthy writers; (2) variability in dynamic features over a series of repetitive signatures fell within 10% of the natural variation of healthy subjects; (3) there was a significant association between increased dynamic signature feature variability and increased dementia severity for stylized and mixed signatures only; and (4) despite significant decline in cognitive status over a 1-year period, dynamic signature features remained stable. Overall, these results suggest that signature writing is preserved in AD. The association between dementia severity and dynamic feature variability among AD subjects with stylized or mixed signatures warrants further research.

The nature of bradykinesia in schizophrenia treated with antipsychotics.

Recognizing drug-induced parkinsonian bradykinesia in psychosis patients can be challenging due to overlapping presentation with psychomotor slowing associated with depression, negative symptoms, or cognitive disturbances. In this study, we apply prior findings on the pathophysiology of bradykinesia in Parkinson's disease to gain an understanding of motor slowing in psychosis patients. Handwriting movements from 57 healthy participants and 70 psychosis patients were recorded on a digitizing tablet. Temporal and kinematic features were extracted from handwritten loops and circles. An independent objective measure based on peak velocity for circles written at maximum speed was used to classify patients as bradykinetic. Using a statistical cut-point derived from normative data, 64% of the patients met criterion for bradykinesia compared with 46% using a conventional observer-based severity rating scale. Bradykinetic patients produced handwriting movements with longer stroke durations, smaller amplitudes and lower peak velocities compared with non-bradykinetic patients. Thirty-six percent of the pen strokes produced by the bradykinetic patients were non-ballistic compare with 20% for the non-bradykinetic patients. The proportion of nonballistic movements observed in handwriting was unrelated to current antipsychotic dose, severity of negative psychosis or depression. The ease-of-use and standardization of a tablet-based approach to quantifying parkinsonian bradykinesia can aid in diagnosing parkinsonian bradykinesia in patients treated with antipsychotics.

Instrument-based assessment of motor function yields no evidence of dyskinesia in adult first-degree biological relatives of individuals with schizophrenia and schizoaffective disorder.

There is accruing evidence of spontaneous dyskinesia in individuals with schizophrenia that is independent of medication exposure. Dyskinetic motor behavior is also present in individuals who are at high risk of schizophrenia and appears to have prognostic value for the development of psychosis. Nonetheless, it remains unclear whether dyskinesia is present in first-degree relatives of individuals with schizophrenia and thus associated with genetic liability for schizophrenia (i.e., an endophenotype), or whether the motor abnormality is a biomarker specific to the disease state spectrum. There is also limited information about links between dyskinesia and clinically relevant phenomena such as symptoms and cognition. Because dyskinesia marking genetic liability is likely to be subtle, we used sensitive instrument-based measurement of handwriting fluency to quantify dyskinesia in medicated individuals with schizophrenia or schizoaffective disorder, unaffected first-degree biological relatives of individuals with schizophrenia and schizoaffective disorder, and control participants. Results indicated that medicated individuals with schizophrenia or schizoaffective disorder exhibited more dyskinesia than both relatives and controls, with no difference between relatives and controls. Dyskinesia in individuals with schizophrenia or schizoaffective disorder was unrelated to current antipsychotic medication dosage, but associated with worse working memory function and greater positive formal thought disorder. These results provide evidence that dyskinesia is not associated with unexpressed genetic liability for schizophrenia.

Internal versus external: oral-motor performance as a function of attentional focus.

PURPOSE: Previous studies (e.g., G. Wulf, M. Höss, & W. Prinz, 1998; G. Wulf, B. Lauterbach, & T. Toole, 1999; for a review, see G. Wulf & W. Prinz, 2001) have reported that limb motor performance is enhanced when individuals adopt an external focus (focusing on the effect of the movement) versus an internal focus of attention (focusing on body parts such as the muscles of the hand). This study tested the hypothesis that the effects of attentional focus on limb performance would also occur in the oral-facial system. METHOD: Two groups of 23 participants were administered both hand and tongue impulse force control tasks in which each group was randomly assigned either an internal or an external focus of attention. Participants were required to exert rapid pressure bursts to achieve a target force level of 20% of their maximal strength. RESULTS: Consistent with limb studies, findings revealed a significant advantage of an external focus (greater accuracy, less variability) for both the hand and tongue control tasks, as opposed to an internal focus of attention. CONCLUSIONS: Results are discussed relative to a constrained-action theory of motor control and future application to speech motor learning.

Impaired hemispheric communication in schizophrenia: a study using the consonant-vowel-consonant task.

The ability of the left and right hemispheres to interact and cooperate in the processing of information is important for normal brain functioning. Some investigators have suggested that this cooperation in functioning occurs through a process called "metacontrol." Because studies have suggested that patients with schizophrenia may have problems with interhemispheric interaction, we considered that it could be informative to study such patients from the viewpoint of interhemispheric cooperation, and more specifically that of metacontrol. To do this we utilized an assessment procedure called the consonant-vowel-consonant (CVC) task, in which nonsense three-letter combinations (trigrams) are presented vertically to the left, right and both visual fields. The pattern of errors can be used to determine the type of processing the hemispheres use under the different conditions of presentation. Previous studies have shown that when trigram information is presented to both hemispheres, the left hemisphere appears to switch into a mode that more resembles right hemisphere processing, and we wished to determine if evidence for this switch in the mode of processing also occurred in a sample of patients with schizophrenia. To determine the specificity of any findings to schizophrenia, we also studied a group of patients with bipolar disorder. For the control and bipolar groups, our results showed the typical finding of superior processing in the right visual field (left hemisphere) over the left visual field, with presentation to both visual fields demonstrating a qualitative error pattern resembling that of the left visual field (right hemisphere). Patients with schizophrenia, however, did not demonstrate this switching into a right hemisphere mode upon bilateral presentation of the trigrams and instead seemed to show no switching, or actually switching into more of a left hemisphere mode. Our results suggest that patients with schizophrenia (but not bipolar disorder) may have abnormalities in the cooperative processing of information when it is presented to both hemispheres, and that this disturbance may reflect problems with metacontrol of hemispheric processing.

Striatopallidal regulation of affect in bipolar disorder.

BACKGROUND: Evidence from the neuroimaging literature suggests that the basal ganglia plays an important role in the regulation of affect. This conclusion stems almost exclusively from group comparisons and it remains unclear whether previous findings can be confirmed from a longitudinal study of mood change. The aim of this study was to increase our understanding of the functional role of the basal ganglia and thalamus in relation to change in affect in patients with bipolar disorder. METHODS: Ten bipolar disorder subjects participated in a functional MRI study. We used a simple motor reaction time task to probe subcortical regions bilaterally. Subjects were scanned twice, once when their self-reported mood ratings indicated hypomania or euthymia and then again when they were in depressed states. RESULTS: Subjects in their euthymic or hypomanic states exhibited increased caudate activity bilaterally and the globus pallidus of the left hemisphere. Longitudinal analyses revealed a significant association between an increase in severity of depression and a decrease in activity in the external segment of the right globus pallidus. CONCLUSIONS: Our findings suggest that the globus pallidus is less responsive during a simple motor task in the depressed compared to the normal or euthymic states in patients with bipolar disorder. These results are consistent with current physiologic models of basal ganglia circuitry in which an increase in caudate activity results in an increase in inhibitory GABAergic outflow to the external globus pallidus and subsequent decrease in thalamocortical excitation and may underlie the clinical manifestations of depression in bipolar disorder. LIMITATIONS: The findings of this study need to be interpreted with caution as correlation coefficients may be overestimated in this small study sample.

Quantitative measurement of handwriting in the assessment of drug-induced parkinsonism.

Monitoring drug-induced side effects is especially important for patients who undergo treatment with antipsychotic medications, as these drugs often produce extrapyramidal side effects (EPS) resulting in movement abnormalities similar to parkinsonism. Scientists have developed several objective laboratory tests to measure and research drug-induced movement disorders, but equipment and tests are complex and costly and have not become accepted in large-scale, multi-site clinical trials. The goals of this study were to test whether a simple handwriting measure can discriminate between individuals with psychotropic-induced parkinsonism, Parkinson's disease, and healthy individuals, and to examine some of the psychometric properties of the measure. We examined pen movement kinematics during cursive writing of a standard word in 13 patients with idiopathic Parkinson's disease (PD), 10 schizophrenia patients with drug-induced parkinsonism (SZ), and 12 normal healthy control participants (NC). Participants were instructed to write the word "hello" in cursive twice, at three vertical height scales. Software was used for data acquisition and analysis of vertical stroke velocities, velocity scaling, and smoothness. There were four important results from this study: (1) both SZ patients with drug-induced EPS and PD participants exhibited impaired movement velocities and velocity scaling; (2) performance on the velocity scaling measure distinguished drug-induced EPS from normal with 90% accuracy; (3) SZ, but not PD participants displayed abnormalities in movement smoothness; and (4) there was a positive correlation between age and magnitude of the velocity scaling deficit in PD participants. This study demonstrates that kinematic analyses of pen movements during handwriting may be useful in detecting and monitoring subtle changes in motor control related to the adverse effects of psychotropic medications.

Do preclinical findings of methamphetamine-induced motor abnormalities translate to an observable clinical phenotype?

This review summarizes the preclinical literature of the effects of methamphetamine (MA) on subcortical dopaminergic and GABAergic mechanisms underlying motor behavior with the goal of elucidating the clinical presentation of human MA-induced movement disorders. Acute and chronic MA exposure in laboratory animal can lead to a variety of motor dysfunctions including increased locomotor activity, stereotypies, diminished or enhanced response times, and parkinsonian-like features. With the exception of psychomotor impairment and hyperkinesia, MA-induced movement disorders are not well documented in humans. This review attempts to draw parallels between the animal and human changes in basal ganglia neurochemistry associated with MA exposure and offers explanations for why a parkinsonian phenotype is not apparent among individuals who use and abuse MA. Significant differences in the expression of neurotoxicity and presence of multiple environmental and pharmacologic confounds may account for the lack of a parkinsonian phenotype in humans despite evidence of altered dopamine function.

Relationship of neuromotor disturbances to psychosis symptoms in first-episode neuroleptic-naive schizophrenia patients.

From the very inception of the modern diagnostic scheme for psychotic disorders, abnormalities in motor function have been observed in these conditions. Despite convergence from multiple areas of research supporting the notion that multiple frontal-subcortical circuits regulate motor and limbic behavior, the precise relationship between motor abnormalities and psychopathology has not been elucidated. The goals of this study were to examine the prevalence of extrapyramidal signs (EPS) in first-episode schizophrenia patients and their relationships to three psychopathological dimensions (positive psychosis syndrome, negative syndrome, and disorganization). We assessed EPS using traditional observer-based as well as quantitative instrumental measures in 39 neuroleptic-naive first-episode schizophrenia subjects. Subjects were followed for 6 months after initiating antipsychotic treatment to examine the stability of motor-limbic relationships. Four main findings emerged from this study. First, depending on the measure used the prevalence of dyskinesia prior to treatment ranged from 13% to 20%. The prevalence of parkinsonism ranged from 18% to 28%. Second, severity of dyskinesia was associated with the positive psychotic syndrome; whereas parkinsonism was associated with the positive psychosis, negative syndrome and disorganization. Third, psychopathology improved significantly across all symptom dimensions following antipsychotic treatment, while EPS remained stable. This suggests that some motor abnormalities in schizophrenia may reflect trait characteristics. Fourth, abnormalities on the pre-treatment instrumental measure of parkinsonism predicted greater improvement on positive psychosis symptoms following treatment (p=0.008). Our findings support the notion that neuromotor disturbances may be a core feature of schizophrenia in a substantial proportion of patients and implicate multiple fronto-striatal circuits regulating limbic and neuromotor behavior in schizophrenia.

Lateralized cognitive dysfunction and psychotic symptoms in schizophrenia.

Our understanding of hemispheric asymmetries in schizophrenia can be attributed to extensive neuropsychological and neuroimaging research on this topic; however, it has yet to be determined whether lateralized cognitive dysfunction represents a single core trait in schizophrenia or whether the lateralized impairments are domain specific. To test whether lateralized deficits are core features in schizophrenia we examined performance across a wide range of lateralized cognitive domains including attention, fluency, recognition memory, perception, and arousal. We also examined the relationship between lateralized impairments and psychotic and affective symptoms to determine whether abnormal hemispheric asymmetries were possibly state-related. The sample consisted of 43 subjects with schizophrenia and 66 normal healthy comparison subjects without psychiatric illness. Schizophrenia subjects exhibited abnormal right hemisphere performance on a test of recognition memory and abnormal left hemisphere performance on a measure of arousal. These findings suggest that lateralized cognitive disturbances in schizophrenia do not represent a single core lateralized deficit. Regarding the symptom analyses, severity of positive symptoms was related to right hemisphere cognitive impairment (including fluency and recognition memory), whereas severity of negative symptoms was related to left hemisphere cognitive impairment (including fluency). Overall, our findings suggest that lateralized dysfunction can occur in both hemispheres in schizophrenia, and that the positive psychotic symptoms may relate more to right hemisphere impairment, whereas negative psychotic symptoms may related more to left hemisphere impairment.

Association of diabetes with dyskinesia in older psychosis patients.

RATIONALE: Older patients treated with antipsychotics are more likely to develop tardive dyskinesia (TD) than younger individuals. Advanced age is also an important risk factor for diabetes, which may be associated with TD. These observations suggest that older diabetic patients may be particularly vulnerable to developing TD. OBJECTIVE: To examine whether older psychosis patients with diabetes exhibit more severe dyskinesia than well-matched patients without diabetes and to test whether there are differences in dyskinesia severity between diabetic patients treated with conventional versus atypical antipsychotics versus those not taking antipsychotic medications. METHOD: Sixty-one psychosis patients with diabetes and 122 case-matched non-diabetic comparison patients were studied. Observer-based and quantitative instrumental measures were administered to assess prevalence and severity of dyskinesia. Raters were unaware of patients' diabetes status. RESULTS: Diabetic patients exhibited significantly more severe TD than non-diabetic comparison patients. Groups did not differ in terms of severity of parkinsonism. Significantly more diabetic (27.9%) than non-diabetic (14.6%) patients met research diagnostic criteria for TD. Diabetic patients treated with atypical antipsychotics at the time of assessment had significantly more severe TD than all other patient subgroups, including patients treated with conventional antipsychotics. Results from the instrumental measures of force steadiness were consistent with observer-based severity ratings. CONCLUSION: The deleterious effect of diabetes on TD in the absence of any effect of parkinsonism supports preclinical studies of glucose-related dopamine hyperfunction and has implications for the pharmacologic management of psychosis in patients with pre-existing diabetes.

A quantitative neuromotor predictor of antidepressant non-response in patients with major depression.

Predicting response to antidepressant medication has been a challenge to clinicians and researchers for decades. Attention has been paid to the role of motor retardation as a putative indicator of treatment response, yet previous findings have been mixed. One reason for this inconsistency may be related to the subjective nature of motor retardation and how it is assessed. In the present study, we adopted a measure of motor programming previously shown to characterize parkinsonian bradykinesia to test whether neuromotor function could predict response to antidepressant treatment. Twenty-eight patients (14 males and 14 females with a mean age of 42.0 years) meeting DSM-IV criteria for a depressive disorder were randomized to receive 8 weeks of treatment with one of three antidepressant medications (sertraline, phenelzine, or bupropion). Treatment outcomes were assessed using the 17-item version of the Hamilton Rating Scale for Depression (HRSD). Patients were considered asymptomatic if their post-treatment HRSD total score was equal to or less than 7. Treatment responders (n=15) had significantly less baseline impairment (P=0.01) on the neuromotor measure than non-responders (n=13). There was a significant relationship between amount of improvement on the HRSD and severity of baseline neuromotor function (r=-0.51; P=0.006). No significant group effects were found for baseline psychomotor slowing or clinical ratings of motor retardation. These results demonstrate that a quantitative measure of motor programming may be a useful predictor of antidepressant non-response.

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder.

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.