Functional magnetic resonance imaging study of regional brain activation during implicit sequence learning in obsessive-compulsive disorder.

BACKGROUND: Corticostriatal circuitry has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The serial reaction time (SRT) task, a paradigm that tests implicit sequence learning, has been used with imaging to probe striatal function. Initial studies have indicated that OCD patients exhibit deficient striatal activation and aberrant hippocampal recruitment compared with healthy control (HC) subjects. Here, we used the SRT and functional magnetic resonance imaging (fMRI) to replicate prior results in a larger sample and to test for relationships between regional activation and OCD symptom dimensions. METHODS: Using SPM99, fMRI-SRT data from 12 OCD and 12 matched HC subjects were analyzed. Symptom dimensions followed a four-factor model scored on a 0- to 10-point scale. RESULTS: For the implicit learning versus random contrast, group by condition interactions revealed aberrant recruitment within the hippocampus as well as orbitofrontal cortex (OCD > HC) but no striatal group differences. However, an inverse correlation was found between striatal activation and specific symptom factors. CONCLUSIONS: These results replicate previous smaller studies showing aberrant hippocampal recruitment in OCD during SRT performance. Although findings of deficient striatal activation in OCD were not replicated, correlation results suggest that this inconsistency may be attributable to differences among OCD symptom dimensions.     

A study of parallel implicit and explicit information processing in patients with obsessive-compulsive disorder

OBJECTIVE: This study examined implicit sequence learning in patients with obsessive-compulsive disorder (OCD) under dual-task conditions. Frontal-striatal networks support implicit learning and are implicated in the pathophysiology of OCD. Neuroimaging data suggest that during implicit learning, OCD patients use neural systems normally active during explicit learning to compensate for striatal dysfunction. METHOD: The authors examined implicit sequence learning in 25 OCD patients and 25 healthy comparison subjects using a dual-task paradigm, with subjects simultaneously engaged in an explicit memory task and an implicit learning task. They predicted that implicit learning in OCD subjects would be disrupted because concurrent explicit information-processing demands would prevent use of compensatory processes. RESULTS: OCD patients failed to show evidence of implicit learning and exhibited a significant deficit in comparison with healthy subjects. CONCLUSIONS: These results are consistent with the hypothesis that concurrent explicit and implicit information-processing demands interfere with implicit learning in OCD patients.     

Functional magnetic resonance imaging evidence for a lack of striatal dysfunction during implicit sequence learning in individuals with animal phobia

OBJECTIVE: This study investigated the neural substrates of implicit sequence learning in subjects with and without small animal phobia, in a follow-up to analogous studies of obsessive-compulsive disorder (OCD). METHOD: Ten subjects with specific phobia and 10 healthy comparison subjects were studied by using a serial reaction time task paradigm and functional magnetic resonance imaging. RESULTS: A main effect of condition (implicit sequence learning versus random sequence) was observed across diagnostic groups in the right striatum, as well as in other regions. In the striatum, the a priori region of interest, there were no significant effects of diagnosis or the interaction of diagnosis and condition. CONCLUSIONS: Brain activation in the striatum of subjects with specific phobia does not significantly differ from that of normal comparison subjects during implicit sequence learning. This suggests different pathophysiological mechanisms for specific phobia in contrast to OCD, in which deficient striatal recruitment has been reproducibly found with this paradigm. This approach offers promise for demonstrating diagnostic specificity across different neuropsychiatric disorders based on the presence or absence of deficient striatal activation.     

Striatal function in generalized social phobia: a functional magnetic resonance imaging study.

BACKGROUND: Although evidence suggests the involvement of the amygdala in generalized social phobia (GSP), few studies have examined other neural regions. Clinical, preclinical, and dopamine receptor imaging studies demonstrating altered dopaminergic functioning in GSP suggest an association with striatal dysfunction. This is the first functional magnetic resonance imaging (fMRI) study to use a cognitive task known to involve the striatum to examine the neural correlates of GSP. We examined whether subjects with GSP had differential activation in striatal regions compared with healthy control subjects while engaged in a cognitive task that has been shown to activate striatal regions reliably. METHODS: Ten adult, unmedicated subjects with a primary DSM-IV diagnosis of GSP and 10 age-, gender-, and education-matched healthy comparison subjects underwent fMRI while performing the implicit sequence learning task. RESULTS: The GSP and healthy comparison subjects did not differ significantly on the behavioral performance of the task. Subjects with GSP, however, had significantly reduced neural activation related to implicit learning compared with healthy comparison subjects in the left caudate head, left inferior parietal lobe, and bilateral insula. CONCLUSIONS: These findings support the hypothesis that GSP is associated with striatal dysfunction and further the neurobiological understanding of this complex anxiety disorder.     

Prefrontal and striatal activation during sequence learning in geriatric depression.

BACKGROUND: Frontostriatal dysfunction is a primary hypothesis for the neurocognitive changes of depression in late life. The aim of the present study was to test this hypothesis with the use of functional magnetic resonance imaging (fMRI) tasks that are known to engage the prefrontal and neostriatal cognitive circuits. METHODS: Twenty-three elderly subjects (mean age, 69.9 years) participated: 11 subjects with a current major depressive episode and 12 nondepressed elderly control subjects. Subjects underwent fMRI while performing a concurrent implicit and explicit sequence learning task. Region of interest (ROI)-based analyses were conducted, focusing on the dorsal anterior cingulate cortex, the dorsolateral prefrontal cortex, and the neostriatum. RESULTS: As expected, both the control and depressed subjects learned the sequence during both implicit and explicit conditions. During explicit learning, decreased prefrontal activation was found in the depressed subjects, along with increased striatal activation. The increased striatal activity in the depressed subjects was due to increased activity on the trials that violated the sequence. During implicit learning, no significant differences were found between the groups in the identified ROIs. CONCLUSIONS: The increased striatal activation on trials that violated the sequence demonstrates a greater response to negative feedback for depressed compared with control subjects. Our observations of significant differences in both prefrontal and striatal regions in the depressed elderly subjects relative to elderly control subjects supports the frontostriatal dysfunction hypothesis of late-life depression.     

Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study

A dysfunction of the fronto-striatal loop has been associated with obsessive-compulsive disorder (OCD). Functional imaging studies suggest that reversal learning is affected by deficits in fronto-striatal brain areas and thus should be impaired in patients with OCD. The authors compared patients with OCD and healthy comparison subjects on a reversal learning task. Correlation analyses and group comparisons showing prolonged reaction times of different response parameters are associated with increasing severity of compulsions. The reversal learning task has been shown to be associated with ventral fronto-striatal brain activation by functional magnetic resonance imaging (fMRI) in healthy comparison subjects. The purpose of this article is to suggest that the reversal learning task can be used as a neuropsychiatric measurement of the ventral fronto-striatal dysfunction in OCD.     

Impaired procedural learning in obsessive-compulsive disorder and Parkinson's disease, but not in major depressive disorder

The striatum has been consistently implicated in the pathophysiology of obsessive-compulsive disorder (OCD), yet, studies assessing the performance of OCD patients in procedural learning tasks, assumed to rely on the intact functioning of the striatum, have yielded inconsistent results. Recently, Rauch et al. [Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T, et al. Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning. J Neuropsychiatry Clin Neurosci 1997;9:568-73] have obtained evidence suggesting that seemingly intact performance of OCD patients in such tasks may be achieved by recruiting systems which in normal subjects are reserved for explicit or declarative, rather than implicit or procedural, processing. The present study assessed procedural learning in OCD patients using a card betting task in which explicit processing impairs, rather than assists, acquisition. In addition, we tested a group of Parkinson's disease (PD) patients, in order to better establish the dependence of the task on procedural learning, and a group of major depressive disorder (MDD) patients, in order to test the possibility that impaired learning in the card betting task may be a result of concurrent depression. The majority of OCD (15/18) and PD patients (14/16) did not acquire the task, whereas MDD patients acquired the task similarly to normal control subjects. These results demonstrate that OCD patients are impaired on a procedural learning task in which explicit processing impairs acquisition. Two different interpretations are suggested: that the striatal system is dysfunctional in OCD, or that inappropriate explicit processing in OCD interferes with the functioning of the striatal system.     

The role of the striatum in implicit learning: a functional magnetic resonance imaging study

Previous research has posited striatal involvement in implicit learning. However, imaging studies have not directly compared learners with non-learners. Using functional magnetic resonance imaging with 15 study participants, we used an implicit learning task previously associated with striatal recruitment. Dorsal and ventral striatum activation was observed in the eight participants who demonstrated implicit learning. Ventral striatum activations occurred to a greater extent in implicit learning versus non-implicit learning participants, and were correlated with the degree of reaction time advantage in implicit learning participants, even after controlling for general decreases in reaction time over time. These findings strengthen the specificity of the striatum in implicit learning and are suggestive of a dissociation of striatal regions relative to elements of implicit learning performance.     

Implicit sequence learning in obsessive-compulsive disorder: further support for the fronto-striatal dysfunction model.

BACKGROUND: Obsessive-compulsive disorder (OCD) is conceived as a disease that implicates dysfunctions in fronto-striatal brain systems. According to this model, performance deficits observed in patients with lesions in these brain areas are hypothesized to be present also in OCD patients. Implicit procedural learning, which refers to the acquisition of motor or nonmotor skills by practice, is one candidate function to test this prediction. METHODS: The serial reaction time task was used to assess implicit sequence learning of 33 patients with a diagnosis of OCD and 27 healthy control participants. In addition, explicit (i.e., conscious) knowledge of the sequence was determined. A subgroup of 24 patients was reassessed after intensive cognitive-behavioral psychotherapy. RESULTS: Implicit sequence learning was significantly reduced in the OCD group by 41%, while explicit learning and verbal abilities were unaffected. The deficit remained stable across time, although symptoms remitted substantially. Depressive symptoms did not account for the finding. Partial explicit knowledge of the sequence was not a predictor of the amount of implicit learning. CONCLUSIONS: Reduced implicit learning appears to be a dissociable trait of OCD patients. The results confirm previous findings and add supportive evidence for the fronto-striatal dysfunction model of OCD.     

Motor inhibition in trichotillomania and obsessive-compulsive disorder

We investigated motor inhibition abilities in trichotillomania (TTM) and obsessive-compulsive disorder (OCD), two disorders characterized by repetitive, intentionally performed behaviors. Performance in a GoNogo experiment of 25 TTM and 21 OCD participants was compared to the performance of 26 HC participants. In contrast to OCD and HC participants, TTM participants tended to perform either 'fast and inaccurate' (indicating poor motor inhibition) or 'slow and accurate'. TTM participants with poor motor inhibition reported a significantly earlier age of TTM onset than those TTM participants who performed well. There was no evidence for motor inhibition deficits in OCD. Based on our data, a subgroup of TTM sufferers seems to be characterized by motor inhibition deficits.     

Striatal recruitment during an implicit sequence learning task as measured by functional magnetic resonance imaging

Prior research has repeatedly implicated the striatum in implicit sequence learning; however, imaging findings have been inconclusive with respect to the sub-territories and laterality involved. Using functional magnetic resonance imaging (fMRI), we studied brain activation profiles associated with performance of the serial reaction time task (SRT) in 10 normal right-handed males. Behavioral results indicate that significant implicit learning occurred, uncontaminated by significant explicit knowledge. Concatenated fMRI data from the entire cohort revealed significant right-lateralized activation in both the caudate and putamen. Analysis of fMRI data from individual subjects showed inter-individual variability as to the precise territories involved, including right as well as left caudate and putamen. Interestingly, all seven subjects who manifested robust learning effects exhibited significant activation within the putamen. Moreover, among those seven subjects, the magnitude of signal intensity change within the putamen correlated significantly with the magnitude of reaction time advantage achieved. These findings demonstrate right-sided striatal activation across subjects during implicit sequence learning, but also highlight interindividual variability with respect to the laterality and striatal subterritories involved. In particular, results from individual subjects suggest that, during the SRT, the reaction time advantage garnered via implicit sequence learning might be predominantly associated with activity within the putamen.     

Visuospatial abilities, memory, and executive functioning in trichotillomania and obsessive-compulsive disorder

Few studies have compared neuropsychological functioning in trichotillomania (TTM) and obsessive-compulsive disorder (OCD). In OCD, most studies suggest abnormal visuospatial abilities, memory, and executive functioning. We compared 23 TTM, 21 OCD and 26 healthy control individuals on neuropsychological tasks assessing these abilities. Neither the TTM nor the OCD groups suffered from generalized neuropsychological deficits compared to the healthy control group. TTM participants showed increased perseveration on the Object Alternation Task suggesting difficulties with response flexibility. OCD participants showed impaired ability to learn from feedback on the Wisconsin Card Sorting Test. Other executive functions, as well as memory and visuospatial abilities were unimpaired in TTM and OCD. Our data suggest that TTM and OCD are characterized by different patterns of neuropsychological dysfunction.     

The role of the basal ganglia and its cortical connections in sequence learning: Evidence from implicit and explicit sequence learning in Parkinson's disease

Implicit (unconscious/incidental) and explicit (conscious/intentional) learning are considered to have distinct neural substrates. It is proposed that implicit learning is mediated by the basal ganglia (BG), while explicit learning has been linked to the medial temporal lobes (MTL). To test such a dissociation we investigated implicit and explicit sequence learning in Parkinson's disease (PD), a disorder characterized by striatal dysfunction. We studied both implicit and explicit learning of a 12-item sequence of target locations in 13 PD patients and 15 age-matched controls. In the implicit sequence learning task all participants completed 10 blocks of a probabilistic serial reaction time (SRT) task in which they were exposed to the sequence without explicit knowledge of it. Participants also completed between 1 and 10 blocks of an explicit sequence learning task in which the sequence was learned deliberately by trial-and-error. Both implicit and explicit sequence learning were significantly impaired in PD patients compared to controls. The results indicate that, in addition to playing a role in implicit sequence learning, the BG and its frontal projections are also involved in explicit sequence learning.     

Cerebral activation in children and adolescents with obsessive-compulsive disorder before and after treatment: a functional MRI study

BACKGROUND: Structural and functional fronto-striatal abnormalities are involved in the pathophysiology of obsessive-compulsive disorder (OCD). The aims of the present study were: (a) to investigate possible regional brain dysfunction in premotor cortico-striatal activity in drug-na?ve children and adolescents with OCD; (b) to correlate brain activation with severity of obsessive-compulsive symptomatology; and (c) to detect possible changes in brain activity after pharmacological treatment. METHOD: Twelve children and adolescents (age range 7-18 years; seven male, five female) with DSM-IV obsessive-compulsive disorder and twelve healthy subjects matched for age, sex and intellectual level were studied. Functional magnetic resonance imaging data were obtained during the performance of simple and complex sequences. RESULTS: Comparing the complex motor condition with the simple control condition, both patients and controls showed a pattern of cerebral activation involving the fronto-parietal cortex and basal ganglia. Compared with controls, OCD patients presented significantly higher brain activation bilaterally in the middle frontal gyrus. After 6 months of pharmacological treatment and with clear clinical improvement, activation in the left insula and left putamen decreased significantly. CONCLUSION: In a paediatric OCD sample that was treatment na?ve and without another psychiatric disorder we showed hyperactivation of the circuits that mediate symptomatic expression of OCD. The cerebral activation decreases after treatment and clinical improvement.     

Deficit in schizophrenia to recruit the striatum in implicit learning: a functional magnetic resonance imaging investigation

In schizophrenia, explicit learning deficits have been well established although it is less clear whether these patients have deficits in implicit learning (IL). IL is thought to depend on intact striatal functioning. This study examined the hypothesis that schizophrenia patients show deficient recruitment of striatal activation during an IL paradigm, relative to performance-matched healthy comparison subjects. Ten subjects with schizophrenia on atypical antipsychotic medication and 10 age, gender, education, and performance matched healthy comparison subjects underwent fMRI while performing an IL task. On the basis of whole-brain and striatal region-of-interest analyses, we found a relative lack of striatal activation in schizophrenia patients. This result is consistent with convergent evidence of striatal dysfunction in schizophrenia.     

Functional imaging of sequence learning in Parkinson's disease

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.     

Implicit learning is intact in adult developmental dyslexic readers: evidence from the serial reaction time task and artificial grammar learning

Previous research yielded equivocal results concerning implicit learning abilities of developmental dyslexic readers. These studies employed a sequence learning task that requires a motor response to each stimulus. However, implicit learning has been often studied using non-motor tasks. Thus, we investigated implicit learning capabilities of adult developmental dyslexic readers in two standard implicit learning paradigms differing in the involvement of the motor system, namely the serial response time task (SRTT) and artificial grammar learning (AGL).Twelve adult developmental dyslexic and twelve age- and sex- matched normal readers were tested. In the serial response time task (SRTT), participants are exposed to a structured display. Learning is measured by comparing response time (RT) to the structured sequence with RT to a random display. In the artificial grammar learning task (AGL), letter strings following a markovian finite state grammar are presented. In a subsequent test phase subjects have to judge new letter strings according to their grammaticality.Learning of the stimulus regularities was found in both tasks and for both groups of subjects. Furthermore, participants were unaware of the underlying stimulus construction principles. Dyslexic readers were unimpaired in SRTT as well as artificial grammar learning relative to normal readers. These findings show that implicit learning is intact in dyslexia. Intact implicit learning capabilities should be taken into account when designing training programs for developmental dyslexic readers.     

A pilot study of brain activation in children with trichotillomania during a visual-tactile symptom provocation task: A functional magnetic resonance imaging study

Objectives

In order to reveal the etiology and pathophysiology of trichotillomania (TTM), it is necessary to investigate which brain regions are involved in TTM, but limited knowledge exists regarding the neurobiology of TTM and the available functional neuroimaging studies of TTM are little. The purpose of the present study was to investigate the specific brain regions involved in the pathophysiology of TTM with symptom provocation task using functional magnetic resonance imaging (fMRI) for children and adolescents with TTM.

Methods

Pediatric subjects who met the DSM-IV TR criteria for TTM (n = 9) and age-, sex-, handedness-, IQ matched healthy controls(HC) (n = 10), ages 9 to 17 years, were recruited for two fMRI experiments; symptom provocation of Visual Only (VO) and Visual and Tactile (VT). They were scanned while viewing two alternating blocks of symptom provocation (S) and neutral (N) movies.

Results

Random effects between-group analysis revealed significant activation in left temporal cortex(including middle and superior temporal gyrus), dorsal posterior cingulate gyrus, and putamen for the contrast S > N in TTM subjects versus HC subjects during the VO session. And TTM subjects demonstrated higher activity in the precuneus and dorsal posterior cingulate gyrus to the contrast S > N during the VT session.

Conclusions

This study provided an objective whole-brain-based analysis that directed researchers to areas that were abnormal in TTM. Using the symptom provocation tasks, we found significant differences in regional brain function between pediatric TTM and HC subjects. However, in the face of modest statistical power, our preliminary findings in TTM need to be replicated in a larger sample. As the functional neuroanatomic circuits involved in TTM remain largely unexplored, future functional neuroimaging studies using other various paradigms may help investigate the neuroanatomic abnormalities of TTM.     

Aberrant ventral striatal responses during incentive processing in unmedicated patients with obsessive-compulsive disorder

Jung WH, Kang D‐H, Han JY, Jang JH, Gu B‐M, Choi J‐S, Jung MH, Choi C‐H, Kwon JS. Aberrant ventral striatal responses during incentive processing in unmedicated patients with obsessive–compulsive disorder. Objective: Obsessive–compulsive disorder (OCD) is characterized by the dysfunction of control and reward mechanisms. However, only few neuroimaging studies of OCD have examined the reward processing. We examined the neural responses during incentive processing in OCD. Method: Twenty unmedicated patients with OCD and 20 age‐, sex‐, and IQ‐matched healthy controls underwent functional magnetic resonance imaging while performing a modified monetary incentive delay task. Results: Compared with controls, patients with OCD showed increased ventral striatal activation in the no‐loss minus loss outcome contrast and a significant positive correlation between the ventral striatal activation and compulsion symptom severity. In addition, patients with OCD showed increased activations in the frontostriatal regions in the gain minus no‐gain outcomes contrast. During loss anticipation, patients with OCD showed less activations in the lateral prefrontal and inferior parietal cortices. However, during gain anticipation, patients with OCD and healthy controls did not differ in the ventral striatal activation. Conclusion: These findings provide neural evidence for altered incentive processing in unmedicated patients with OCD, suggesting an elevated sensitivity to negatively affect stimuli as well as dysfunction of the ventral striatum.     

Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder

Functional and structural neuroimaging studies have implicated the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD), although no consensus has been established. These brain regions have not been investigated in refractory OCD patients. Volumes of the hippocampus, and amygdala were measured by magnetic resonance imaging (MRI) in a sample of 14 refractory OCD patients and 14 healthy comparison subjects. The mean left and right hippocampal and amygdala volumes of the patients were smaller than those of the healthy controls. OCD severity was not correlated with amygdala volumes but was related to the left hippocampus. Duration of illness was correlated with both hippocampus and left amygdala. Our findings suggest that hippocampus and amygdalar abnormalities can be considered in refractoriness to OCD.